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 1-16, of record 6/17/2024, are pending and subject to prosecution.
Priority
The instant application is a national stage entry of PCT/EP2022/087224 (filed 12/21/2022). Acknowledgement is made of the applicant’s claim for foreign priority to EPO application 21216354.7 (filed 12/21/2021).
Drawings
The drawings are objected to because view number must be preceded by the abbreviation “FIG.” See 37 CFR 1.84(u). 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.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code in ¶0012 of the application’s PG Pub. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP 608.01.
The use of the terms TURBO DNase, RNeasy, and QuantiTect , 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 terms.
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
Claims 3, 5-7, 9-13, and 15-16 are objected to because of the following informalities:
In claims 3 and 5-6, “at least two MS2 coat proteins” should be replaced with “2xMS2CP”.
In line 10 of claim 6, “glycin” should be replaced with “glycine”. Claim 6 also lacks a conjunction after “linker” in line 10.
In claims 7, 9-11, and 15, “target site (TS)” should be replaced with “TS”.
In line 6 of claim 10, “arranged in 5’ of directly adjacent” should be rewritten as “arranged 5’ and directly adjacent to” or the like for improving clarity.
In line 4 of claim 11, “identity” should be inserted after “95%”.
In line 1 of claims 12-13, “particle” should be inserted after “alpharetrovirus-based”, and “particles” in line 4 should be replaced with “particle”.
In claim 15, “2xMS2CP” denotes at least one MS2 coat protein dimer, while “2xMS2CP” denotes at least two MS2 coat proteins in parent claim 1. Because the scope of “2xMS2CP” is different in dependent claims 15-16, the applicant should use a different abbreviation for these claims.
Appropriate correction is required.
Claim Interpretation
Claim 1 is interpreted as requiring 1) a protein component comprising alpharetroviral domains that consist of MA-p2-p10-CA-NC-PR, wherein each of MA, p2, p10, CA, NC, and PR is a domain; 2) a linker of 7 to 25 amino acids; 3) at least two MS2 coat proteins; 4) a pseudotyping protein; and 5) at least one RNA construct encoding a gene of interest linked to at least one target site in association with the protein component.
Because claim 6 lacks a conjugation joining the claim elements, the broadest reasonable interpretation of the claim requires the alpharetrovirus-based particle to be characterized in that: 1) the alpharetroviral domains have an amino acid sequence having at least 90% identity to the amino acid sequence encoded by nucleotides No. 1462 to 3573 of SEQ ID NO: 12 (MA-p2-p10-CA-NC-PR) or to the amino acid sequence encoded by nucleotides No. 1462 to 3186 of SEQ ID NO: 1; 2) the linker of 7 to 25 amino acids has an amino acid sequence having at least 90% identity to the amino acid sequence encoded by nucleotides No. 3187 to 3207 of SEQ ID NO: 1 or to the amino acid sequence encoded by nucleotides No. 3574 to 3594 of SEQ ID NO: 12, or is a glycine linker; or 3) the at least two MS2 coat proteins comprise an amino acid sequence having at least 90% identity to the amino acid sequence encoded by nucleotides No. 3613 to 4389 of SEQ ID NO: 12 or encoded by nucleotides No. 3223 to 3999 of SEQ ID NO: 1.
Claim 11 recites “the target site… a nucleotide sequence of at least 90%, preferably at least 95% to at least one sequence selected from nucleotides 1943 to 1965 and/or nucleotides 1982 to 2004 of SEQ ID NO: 2, of nucleotides 1681 to 1701 and/or nucleotides 1751 to 1771 of SEQ ID NO: 3, of nucleotides 1755 to 1775 and/or nucleotides 1794 to 1814 of SEQ ID NO: 14, of nucleotides 5697 to 5719 and/or nucleotides 5736 to 5758 of SEQ ID NO: 5, of nucleotides 2337 to 2359 and/or nucleotides 2376 to 2398 of SEQ ID NO: 6”. The broadest reasonable interpretation of this limitation is a sequence comprising two or more contiguous nucleotides having at least 90% identity to the enumerated sequences. The claim also recites “the 2×MS2CP has at least 90%, preferably at least 95% identity to an amino acid sequence encoded by nucleotides No. 3223 to 3999 of SEQ ID NO: 1”. The broadest reasonable interpretation of this limitation is a sequence comprising two or more contiguous amino acids having at least 90% identity to the enumerated sequence.
Claim 13 recites the limitation “an envelope glycoprotein, which may target the particles to specific cell types and guide its target range”. Because the claim does not appear to require that the envelope glycoprotein target the particles to specific cell types and guide its target range, this claimed feature of the envelope glycoprotein is interpreted as being optional.
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 10-11, 14, and 16 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 10 recites the limitation “the hairpin sections of two TS domains” in line 5. There is insufficient antecedent basis for this limitation in the claim.
In claim 11, the term “preferably” renders the claim indefinite because it is unclear whether the limitation(s) following the term are part of the claimed invention. See MPEP 2173.05(d).
Claim 14 recites a use but fails to describe any active, positive steps delimiting how the use is practiced. The claim is indefinite because it attempts to claim a process without setting forth any steps involved in the process.
Claim 16 recites the limitation “its protease site” in line 2. There is insufficient antecedent basis for this limitation in the claim. Claim 16 also recites the limitation “the protein” in line 2, and because parent claim 15 recites “a protein component”, “at least one MS2 coat protein dimer”, and “a pseudotyping protein”, it is unclear which element is being referenced.
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.
Claim 14 is rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter.
The claim does not fall within at least one of the four categories of patent eligible subject matter because “use” claims that do not purport to claim a process, machine, manufacture, or composition of matter fail to comply with 35 U.S.C. 101.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. The 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 1-7 and 12-16 are rejected under 35 U.S.C. 103 as being unpatentable over Prel et al. (Molecular Therapy—Methods & Clinical Development, 2015) in view of Weldon et al. (Journal of Virology, 1990), evidenced by Schur et al. (Journal of Virology, 2015), and in view of Ling et al. (Nature Biomedical Engineering, 2021) and Pettit et al. (Journal of Virology, 2002).
Regarding claims 1-3, 5-7, and 12-16: Prel et al. teach chimeric retroviral virus-like particles (VLPs) comprising the MS2 coat protein gene sequence fused to the HIV-1 Gag precursor sequence (See fig. a). The VLPs were pseudotyped with VSV-G (which reads on “pseudotyping protein” and “envelope glycoprotein”) (See page 8, col. 2, full ¶1). The VLPs were used to package mRNAs for luciferase (which reads on “a coding sequence for an enzyme”), Cre recombinase, and a hepatitis C virus replicon (which reads on “self-amplifying RNA replicons”) that comprised multiple copies of the MS2-stem-loop (which reads on “at least one RNA construct encoding a gene of interest linked to at least one target site” within host cells (which read on “producer cell”) (See fig. 1-4). Prel et al. teach significant transduction in vitro and in vivo with the VLPs and suggest that the VLPs could have immunotherapeutic applications (which reads on “medical treatment”) (See page 1, col. 2, full ¶1 and page 11, col. 2, full ¶1). Prel et al. teach a lentiviral-based VLP rather than an alpharetrovirus-based one and do not teach the presence of a linker or at least two MS2 coat proteins.
Weldon et al. teach the generation of chimeric Gag proteins for incorporating foreign antigens into retroviral particles (See Abstract). The Saccharomyces cerevisiae iso-1-cytochrome c was fused to the Rous sarcoma virus (which reads on “alpharetrovirus”) Gag, which consists of MA-p2-p10-CA-NC-PR (See fig. 1 and 3). Chimeric Gag was efficiently packaged and released from cells (See page 4169, col. 2, full ¶2; page 4170, col. 1, ¶1; and fig. 7). Weldon et al. also suggest that foreign proteins of interest could be released from Gag by inclusion of a protease cleavage site at the junction of the two proteins (See page 4177, col. 2, full ¶3).
Ling et al. teach the generation of a lentiviral platform for delivery of Cas9 mRNA and sgRNA within a single particle (See Abstract and fig. 2). Monomeric (1x) or dimeric (2x) MS2 coat protein was inserted at either Gag-Pol terminus (See fig. 1a). An HIV-1 protease signal was inserted between the foreign and native proteins to release MS2 (which reads on “the… domains by hydrolysis of the linker are separated from the at least two MS2 coat proteins” and “proteolyzed at its protease site to separate the domains from the at least one MS2 coat protein”) (See page 145, col. 2, ¶1).
Pettit et al. teach that the Rous sarcoma virus NC/PR cleavage sequence is PAVSLAM (which reads on “a linker of 7-25 amino acids” and “viral protease site”) (See page 10231, col. 2, full ¶1), which is identical to the amino acid sequence encoded by nucleotides 3187-3207 of instant SEQ ID NO 1 (See alignment below).
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It would have been obvious to one having ordinary skill in the at prior to the effective filing date of the claimed invention to modify the method of Prel et al. to use Rous sarcoma virus Gag in place of HIV-1 Gag. One would have been motivated to make this modification because combining prior art elements according to known methods to yield predictable results is considered to be prima facie obvious. See MPEP 2143(I). Because Weldon et al. demonstrate that Rous sarcoma virus is permissive for the fusion of Gag to foreign protein and its packaging into particles (See fig. 7), one of ordinary skill could reasonably expect that an MS2 coat protein could be similarly appended for generating VLPs.
It also would have been obvious to incorporate a dimeric MS2 coat protein and a protease signal, as taught by Ling et al., into the construct. Ling et al. teach the dimeric MS2 coat protein as an alternative to the monomeric form (See page 145, col. 2, ¶1-2). Alternative embodiments constitute prior art. See MPEP 2123(II). Additionally, one of ordinary skill would have found it obvious to specifically use a cleavage site recognized by the Rous sarcoma virus protease (expressed by Gag), such as that taught by Pettit et al., to link the Rous sarcoma virus Gag and the MS2 coat protein to ensure cleavage.
Regarding claim 4: Following the discussion of claims 1-3, 5-7, and 12-16, Weldon et al. teach that the Rous sarcoma virus Gag is cleaved by its protease to form separate MA, p10, CA, NC, and PR proteins (See page 4169, col. 1, ¶2). The teachings of Schur et al. provide evidence that the viral p2 proteins are also cleaved (See page 10295, col. 1, full ¶2 and col. 2, ¶1). The native Gag protein therefore reads on “comprising a protease site between each of the alpharetroviral domains”.
Claims 1-8, 10, and 12-16 are rejected under 35 U.S.C. 103 as being unpatentable over Prel et al. (Molecular Therapy—Methods & Clinical Development, 2015) in view of Weldon et al. (Journal of Virology, 1990), evidenced by Schur et al. (Journal of Virology, 2015), and in view of Ling et al. (Nature Biomedical Engineering, 2021) and Pettit et al. (Journal of Virology, 2002), further in view of Knopp et al. (Molecular Therapy—Nucleic Acids, 2018), of record in IDS dated 6/17/2024.
The teachings of Prel et al., Weldon et al., Schur et al., Ling et al., and Pettit et al. are set forth in the rejection above and are incorporated herein in their entirety.
Regarding claims 8 and 10: Following the discussion of claims 1-7 and 12-16, Prel et al., modified by Weldon et al., evidenced by Schur et al., and modified by Ling et al. and Pettit et al., render obvious a chimeric alpharetrovirus particle that can be used for CRISPR applications. Ling et al. teach linkage of the Cas9-encoding mRNA to MS2 stem-loops but do not expressly teach a noncoding RNA construct linked to at least one target site.
Knopp et al. teach all-in-one chimeric gammaretroviral particles for CRISPR/Cas9 RNA delivery (See Abstract). MS2 stem-loop target sites were incorporated into expression plasmids for both Cas9 and sgRNA (which reads on “a non-coding RNA”) after those genes (which reads on “the RNA construct contains a sgRNA which is arranged in 5’ of directly adjacent to at least two target sites”) and in front of PRE elements and polyA tails (which reads on “to the end of which a polyT stretch is linked”) (See fig. 1C-D).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of Prel et al., modified by Weldon et al., evidenced by Schur et al., and modified by Ling et al. and Pettit et al., to link the nucleotide encoding sgRNA to MS2 stem-loop target sites, as well. One would be motivated to make this modification because Knopp et al. suggest that doing so enhances editing activity (See page 259, col. 1, ¶1). There would be a reasonable expectation of success in making this modification because sgRNA constructs could be readily modified in such a manner.
Claims 1-10 and 12-16 are rejected under 35 U.S.C. 103 as being unpatentable over Prel et al. (Molecular Therapy—Methods & Clinical Development, 2015) in view of Weldon et al. (Journal of Virology, 1990), evidenced by Schur et al. (Journal of Virology, 2015), and in view of Ling et al. (Nature Biomedical Engineering, 2021) and Pettit et al. (Journal of Virology, 2002), further in view of Knopp et al. (Molecular Therapy—Nucleic Acids, 2018), of record, further in view of Bouille et al. (US 20180135025 A1).
The teachings of Prel et al., Weldon et al., Schur et al., Ling et al., Pettit et al., and Knopp et al. are set forth in the rejections above and are incorporated herein in their entirety.
Regarding claim 9: Following the discussion of claims 1-8, 10, and 12-16, Prel et al., modified by Weldon et al., evidenced by Schur et al., and modified by Ling et al., Pettit et al., and Knopp et al., render obvious a chimeric alpharetrovirus particle comprising a target site-linked sgRNA but do not expressly teach the inclusion of multiple target site-linked sgRNAs in the particle.
Bouille et al. teach retroviral particles for encapsidating multiple nonviral RNAs (See Abstract). The RNAs are each linked to an encapsidation sequence recognized to a binding domain that can be fused to the Gag polyprotein (See ¶0024). The encapsidation sequence can be the MS2 stem-loop motif, and the binding domain can be the MS2 coat protein (See ¶0031-0032). The RNAs can be sgRNA (See ¶0049).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of Prel et al., modified by Weldon et al., evidenced by Schur et al., and modified by Ling et al., Pettit et al., and Knopp et al., to incorporate multiple different sgRNAs, as suggested by Bouille et al. One would have been motivated to make this modification because Bouille teach that it enables delivery of at least two RNAs by a single infection, reducing the risk of cell toxicity (¶0025 and 0515). There would be a reasonable expectation of success in doing so because multiple MS2 stem-loop-linked sgRNAs could be readily packaged in chimeric alpharetrovirus particles.
Claims 1-16 are rejected under 35 U.S.C. 103 as being unpatentable over Prel et al. (Molecular Therapy—Methods & Clinical Development, 2015) in view of Weldon et al. (Journal of Virology, 1990), evidenced by Schur et al. (Journal of Virology, 2015), and in view of Ling et al. (Nature Biomedical Engineering, 2021) and Pettit et al. (Journal of Virology, 2002), further in view of Knopp et al. (Molecular Therapy—Nucleic Acids, 2018), further in view of Bouille et al. (US 20180135025 A1), further in view of Plevka et al. (Protein Science, 2008).
The teachings of Prel et al., Weldon et al., Schur et al., Ling et al., Pettit et al., Knopp et al., and Bouille et al. are set forth in the rejections above and are incorporated herein in their entirety.
Regarding claims 8 and 10: Following the discussion of claims 1-7 and 12-16, Prel et al., modified by Weldon et al., evidenced by Schur et al., and modified by Ling et al., Pettit et al., Knopp et al., and Bouille et al. render obvious a chimeric alpharetrovirus particle that can be used for CRISPR applications. Bouille et al. teach the RNA stem-loop motif of MS2 as comprising a sequence identical to nucleotides 1982-2004 of instant SEQ ID NO 2 (See ¶0031, SEQ ID NO 1, and alignment below).
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However, none of the prior art references expressly teach the MS2 coat protein sequence.
Plevka et al. teach the wild-type MS2 coat protein as comprising an amino acid sequence 99.6% identical to the sequence encoded by nucleotides 3223-3999 of instant SEQ ID NO 1 (See fig. 5).
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It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of Prel et al., modified by Weldon et al., evidenced by Schur et al., and modified by Ling et al., Pettit et al., Knopp et al., and Bouille et al., to substitute the MS2 stem-loop sequence taught by Bouille et al. and the MS2 coat protein sequence taught by Plevka et al. Substitution of one known element for another known element is considered to be prima facie obvious, absent a showing that the substitution yields more than predictable results. See MPEP 2143(I)(B).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JENNIFER S SPENCE, whose telephone number is 571-272-8590. The examiner can normally be reached M-F 8:30-5:30.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Christopher M Babic, can be reached at 571-272-8507. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JENNIFER S SPENCE/Examiner, Art Unit 1633
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