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 .
Preliminary Amendment
The preliminary amendment dated 03/08/2024 has been entered. Claims 56-74 and 153-158 are pending and under examination.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. The earliest possible effective filing date for the instant claims is January 27, 2021 based on the filing date of the provisional application 63/142,441.
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 (FIG. 1A, 1B) 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.
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.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 57 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 57 recites the limitation ",,,wherein the percentage of the isolated endogenous retroviral capsid that assembles to form the capsid is determined by size exclusion chromatography.” The first capsid term is confusing because a capsid cannot assemble to form a capsid, This claim has been interpreted to read as follows: “…..wherein the percentage of the isolated endogenous retroviral capsid polypeptide that assembles to form the capsid is determined by size exclusion chromatography.”
Appropriate correction is required.
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.
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 56-67 69-70, 73-74, 153 and 155-158 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang (US 2020/0347100 Al published on November 5, 2020, IDS citation: US patent application publication 1) and Suffian (ACS Appl. Nano Mater. 2018, 1, 3269−3282 and Supplemental Information) in view of Lingappa (Methods Mol Biol. 2009 ; 485: 185–195).
Zhang teaches an engineered occurring polypeptide that self-assembles into an export compartment [0005] The engineered polypeptide is from a virus, such as retrovirus [0078] (instant claim 56). Zhang also teaches a method of producing non-naturally occurring capsids (export compartments) (instant claim 56 and 59) for transferring nucleic acids and/or proteins (the cargo of instant claims 59 and 63) to a cell. The method includes expressing in a population of cultured cells a Gag like protein (reads on the engineered endo-gag polypeptide of claim 64), nucleic acids and/or proteins (instant claim 56(a), 59(a) and 64); obtaining a cell lysate from the population of cells; (which would include the polypeptide) and purifying capsids from the cell lysate. [0023]. This reads on the claim 56 limitation “…(b) isolating the endogenous retroviral capsid polypeptide, wherein, at least about 5% of the isolated endogenous retroviral capsid polypeptide assembles to form the capsid”. Because Zhang teaches that the polypeptides can self-assemble into capsids inherently, at least about 5% of the self-assembly polypeptides would self-assemble into capsids so capsids can be purified. In addition, the term “about” is not defined in the instant specification, therefore the “at least about 5%” could be less than exactly 5%. Zhang also teaches that capsids can be purified by any means known in the art, including size exclusion chromatography (SEC) [0109]. This reads on instant claim 57 limitation “….wherein the percentage of the isolated endogenous retroviral capsid polypeptide that assembles to form the capsid is determined by size exclusion chromatography”, since SEC separates molecules based on their size, a purification step using SEC will allow to determine the amount of isolated polypeptide and the amount of capsids. Zhang also teaches the isolation of the retroviral capsid polypeptide that self-assembles into a capsid (Zhang’s claim 33 and 34) as required by instant claims 56(b) and 59(b) and that the polypeptide can be a gag-like protein ([0008] and [0018]) including PMNA and PMNA2 ([0009] and [0020),] (instant claims 64-66).
Zhang does not teach the steps of capsid disassembly/reassembly to upload the cargo (instant claims 59-63) or the conditions to perform those steps (instant claims 69-70, 73-74 and 153 and 155-158). Zhang does not teach SDS-PAGE to determine purity or yield (instant claims 58, 60-62 and 67).
Suffian teaches the capsid disassembly/reassembly to upload the cargo (instant claims 59-63) in 2.3.3 section: Method III: Disassembly/Reassembly Using EGTA/CaCl2. (page 3270). modified HBV core particles (capsids) were incubated in a disassembly buffer (instant claims 59(c) and 63(a)) containing 50 mM Tris, 150 mM NaCl, 1 mM EGTA (solubilizing agent as required by instant claim 153), and 20 mM dithiothreitol (DTT) (DTT is a reducing agent as required by instant claims 69 and 70), at 1:1 volume ratio for 1 h at 20 °C (instant claim 158) for siRNA (cargo) encapsulation (instant claims 59(d) and 63(b)). To reassemble the particles (instant claims 59(e) and 63(c), 0.1 M CaCl2 was slowly added to the mixture to reach a final CaCl2 concentration of 10 mM. Since CaCl2 is a salt, the addition of CaCl2 for reassembly reads on instant claims 73 and 74. A depiction of this method of capsid disassembly/reassembly is shown in Figure S1 Method III (Zhang Supplemental Information).
Suffian also teaches an alternative method for capsid disassembly/reassembly in 2.3.1 section: Method III: Disassembly/Reassembly Using Urea/NaCl. (page 3270). modified HBV core particles (capsids) were dialyzed against 1 L of disassembly buffer containing 1.5 M urea (a chaotropic agent as required by instant claims 155-157), 0.5 M LiCl, 50 mM Tris, and 5 mM dithiothreitol (DTT) (instant claim 69, 70 and 157) at 4 °C overnight (instant claim 158) to disassemble the particles into monomers (instant claims 59(c) and 63(a)). A depiction of this method of capsid disassembly/reassembly is shown below in Figure S1 Method I (Zhang Supplemental Information).
Suffian does not teach SDS-PAGE to determine purity or yield (instant claims 58, 60-62 and 67).
Lingappa teaches the assembly of immature HIV-1 (a retrovirus) capsids using a cell-free system (title) (instant claim 56(a)). Purified recombinant Gag polypeptides (instant claim 64), at high concentrations, were found to self-assemble into spherical particles (page 1 Introduction, 2nd paragraph). Lingappa found that only 20-40% of newly-synthesized Gag polypeptides assemble into completed immature HIV-1 capsids in the cell-free system and the remainder of newly synthesized Gag polypeptides are arrested in the form of various assembly intermediates (page 5 , 2nd paragraph). The 20-40% completed immature capsids read on instant claim 56(b) (at least about 5% of the isolated endogenous retroviral capsid polypeptide assembles to form the capsid); instant claim 58 (at least 20% of the isolated endogenous retroviral capsid polypeptide assembles to form the capsid); instant claim 60 (isolated polypeptide is at least partially present in a capsid form prior to step (c)); instant claim 61 (at least about 5% of the polypeptide that is present in capsid form before step (c) is disassembled after step (c). That is, at least about 5% of the previously assembled capsids would disassemble under conditions commonly optimized to strongly promote disassembly) and instant claim 62 at least about 5% of the polypeptide that is present in disassembled form after step (c) is present in capsid form after step (d). That is, 20-40% HIV capsids self-assemble previously and thus it can be expected that at least 5% would reassemble under favorable and optimized conditions). Lingappa also teaches the use of SDS-PAGE to evaluate the capsid yield, in this case 20-40%, after purification (page 6, 3.4 SDS-PAGE and Autoradiography Section) (instant claim 67).
PNG
media_image1.png
831
692
media_image1.png
Greyscale
It would have been obvious to one of ordinary skill in the art to combine the teachings of Zhang with Suffian to develop a method of making capsids by expressing and isolating a self-assembly retroviral capsid proteins (PMA2), and then disassembling and reassembling the capsid under optimized conditions to load the cargo. One of ordinary skill would have been motivated to do so because both Zhang and Suffian use viral capsid proteins with the goal of delivering a cargo It would further be obvious to combine the teachings of Zhang and Suffian with Lingappa to determine parameters such as purity or yield by incorporating the use of SDS-PAGE to the method of making capsids, to develop. One of ordinary skill would have been motivated to do so because Lingappa teaches a method of making capsids in a cell-free system. There would be a reasonable expectation of success because as shown by Zhang, Suffian and Lingappa, there are several ways to successfully isolated self-assembled capsids loaded with a cargo.
It would further be obvious with that the percentages of isolated polypeptides, percentages of polypeptides assembled into capsids, capsid disassembling into polypeptides, purity, salt concentrations, incubation temperatures or other measurements are clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize. It would have been customary for an artisan of ordinary skill to determine the optimal amount of each ingredient needed to achieve the desired results. The principle of law states from MPEP 2144.05: "The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages." (Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382); Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 2
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claims 56, 59, and 67-68, are rejected under 35 U.S.C. 103 as being unpatentable over Zhang, Suffian and Lingappa in view of Conner (US 2024/0066146 A1, priority date December 18, 2020) and Malvern (Screen captures from YouTube video clip entitled "Introduction to MADLS: Multi-Angle Dynamic Light Scattering," 1 pages, uploaded on May 23, 2018 by user " Malvern Panalytical". Retrieved from Internet: https://www.youtube.com/watch?v=-5ffQUbGjGk&t=1s)
The teachings of Zhang, Suffian and Lingappa have been discussed above and incorporated herein.
Zhang, Suffian and Lingappa do not teach the use of multi-angle dynamic light scattering (MADLS) to determine homogeneity (instant claim 68).
Conner teaches the use of MADLS in a composition comprising recombinant AAV which comprises an AAV6 capsid protein ([0017]. MADLS is used in this case to measure capsid concentration [0124] (instant claim 68). In addition, Conner teaches that, capsid purity can be measured by SDS-PAGE( [0071] and [0079). Table 3 and 7 disclose the results under various situations with capsid purity being 100%. (instant claim 67).
Conner does not teach the use of MADLS for homogeneity calculations.
Malvern teaches the use of MALDLS to analyze the properties of proteins, polymers, colloids and nanomaterials. This instrument can determine particle size distribution, diffusion rates, and other critical characteristics of nanoparticles (video description. At the 2:25 timestamp the narrator explains how to resolve the different size distribution in a population. That is, the population homogeneity as required by instant claim 68.
It would have been obvious to one of ordinary skill in the art to combine the teachings of Zhang, Suffian and Lingappa in view of Conner and Malvern to incorporate the use of MADLS in the method of making capsids to measure homogeneity . One of ordinary skill would have been motivated to do so because Zhang, Suffian, Lingappa and Conner teach methods of making and/or analyzing capsids (including MADLS as taught by Conner) and Malvern teaches the uses of MADLS. There would be a reasonable expectation of success because all these techniques have proven to be efficient in making capsids and are routinely utilized in labs all over the world.
It would further be obvious with that purity or other measurements are clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize. It would have been customary for an artisan of ordinary skill to determine the optimal amount of each ingredient needed to achieve the desired results. The principle of law states from MPEP 2144.05: "The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages." (Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382); Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 2
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claims 56, 59, 71-72 and 154 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang and Suffian in view of Kuznetsov (J. Virol, Nov. 2003, p. 11896–11909) and Expert-Bezançon (Biophysical Chemistry 100 (2003) 469–479)
The teachings of Zhang and Suffian have been discussed above and incorporated herein. Zhang and Suffian do not teach the addition in the disassembly buffer of a non-denaturing detergent such as CHAPS (instant claim 71 and 72) or sulfobetaines (instant claim 154).
Kuznetsov teaches that Isolated HIV virions can be disrupted by exposure to mild neutral detergents (CHAPS) at concentrations from 0.25 to 2.0% (abstract) and intact virions, partially disrupted virions, and degradation products were simultaneously present (page 11902 Disruption of virions by exposure to nonionic detergents Section, 1st paragraph) as required by instant claim 71 and 72. Kuznetsov does not teach about sulfobetaines.
Expert-Bezançon teaches that non-detergent sulfobetaines had been shown to prevent aggregation (that is, assembly if present in a disassembly buffer with capsids) and improve the yield of active proteins when added to the buffer during in vitro protein renaturation (abstract and entire article) (instant claim 154)
It would have been obvious to one of ordinary skill in the art to combine the teachings of Zhang, Suffian, Kuznetsov and Expert-Bezançon to incorporate detergents such as CHAPS or non-detergents such as sulfobetaines to the method of making capsids. One of ordinary skill would have been motivated to do so because these chemicals can aid in the process of disassembly of capsids and prevent aggregation. There would be a reasonable expectation of success because these are known properties of these types of chemicals.
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to IMMA BARRERA whose telephone number is (571) 272-0674. The examiner can normally be reached Monday - Friday 9 to 5.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Janet Andres can be reached on (571) 272-0867. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/IMMA BARRERA/
Examiner, Art Unit 1671
/JANET L ANDRES/Supervisory Patent Examiner, Art Unit 1671