DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1-2,7,11,18,21,24,27,30,43-44,48-49,56-59 and 65 are pending.
This application claims priority to a provisional application U.S. provisional application 63/265,429 filed 12/15/2021.
Information Disclosure Statement
An IDS filed 3/8/2024 has been identified and the documents considered. The signed and initialed PTO Form 1449 has been mailed with this action.
Claim Objections
Claims are objected to because of the following informalities: claim 48 refers to a number of cell lines using abbreviations wherein MPEP §2429 states that Applicant only use abbreviations that are specifically defined in "WIPO Standard ST.25 (1998)" or that are well known and would be clear to someone who had not read the invention description.
Alternatively, once the abbreviation has been established subsequent full spelling is not necessary. This will be relevant upon allowance for claims 43 and 59. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-2,7,11,18,21,24,27,30,43-44,48-49,56-59 and 65 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. The dependent claims are included in the rejection because they fail to address or clarify the basis of the rejection as discussed in detail for the independent claims.
Claim 1 recites the limitation "the producer cell" in line 8. There is insufficient antecedent basis for this limitation in the claim. There are two occurrences of the producer cell by line 8 and it is not clear to which line 8 refers. The producer cell is produced in step (a) and cultured in a first culture media in step (b) and in step (c) a second culture media. It is unclear if the first and second are sequentially conducted or if they are simultaneously performed and therefore it is not clear if the particles are produced from the first or the second given the lack of unique reference to each. This issue arises in claim 43, line 12-13.
Claim 1 is incomplete in line 19 by reciting that the rAAV particles comprise an rAAV genome with a transgene. The genome alone is encoded on the polynucleotide in line 2-3 and hence it is not clear form where the transgene arose in line 9. This arises in claim 43, line 14.
Claim 56 recites the limitation "the inner cell mass" in claim 49. There is insufficient antecedent basis for this limitation in the claim. Therea re at least two references to a nucleic acid vector, the first a nucleic acid vector and the other is “the same nucleic acid vector”. The later indicates that polynucleotides are on the same vector but it is not clear tht it is the same as that in line 5.
Claim 57 recites the limitation "the polynucleotide(s) or nucleic acid vector(s)" in claim 1. There is insufficient antecedent basis for this limitation in the claim.
Claim Rejections - 35 USC § 112, first paragraph
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.
Claims 1-2,7,11,18,21,24,27,30,43-44,48-49,56-59 and 65 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claims are drawn to a method for producing rAAV particles. The claims require “introduction” of a polynucleotide encoding an AAV genome into any mammalian cell. That this is any mammalian cell does not provide sufficient function in order to produce a particle. It appears that applicants intend that by genome is meant rep and cap genes as well as ITRs. However, the cell or method requires that there be consideration of cell type as well as inclusion of helper functions. AAV relies on host cells and helper virus to replicate. As well, when forming an AAV particle with a transgene, there must be a transfer vector with ITRs flanking the transgene (see figure 1 of Aponte-Ubillus et al, Applied Microbiology and Biotechnoloy, 2018, pages 1045-1054). These sequences are transfected into a host cell. The provision of any mammalian cell and an rAAV genome does not provide the adequate structure to produce a rAAV particle with a transgene. Hence, the claims are drawn to a structural molecule that must also have functional properties to produce the rAAV with transgene but the description does not provide for this. A list of cells provided for in claim 48 does not remedy this. This is a limited descriptive element wherein the claims broadly and incompletely claim the inventive elements.
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 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.
Claims 1, 7, 11, 30, 37, 41, 48, 49, 56 and 65 are rejected under 35 U.S.C. 103 as being unpatentable over Kyostio-Moore (WO 2022072657, efd 1/10/2020) in view of Hanak and Truran (US 2021/0355503).
Kyostio-Moore teaches a method of producing rAAV comprising PAH as a transgene [[0115]]. Mammalian cells are transfected with the nucleic acid sequences for the rAAV and cultured [[0110]]. The method can be performed over a range of times and temperatures [[0117]].
To this end, Hanak and Truran provide a method of manufacture for rAAV for therapeutic purposes. This method is shown below.
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The method provides for a first culture with a first temperature and first period of time (transfection media) and a second of such (virus release solution) wherein the second temperature is 39C as required by claim 1.
Based on such teachings, it would have prima facie been obvious to one of ordinary skill in the art at the time the invention was made to incorporate the method of manufacture as taught by Hanak and Truran for producing the virus of Kyostio-Moore. Such a modification would have resulted in a method encompassed by claim 1. As noted above: 1) Kyostio-Moore teaches rAAV for therapeutic purposes; 2) Hanak and Truran teach manufacture methods for therapeutic rAAV. Thus, a person of ordinary skill in the art, absent evidence to the contrary, would have reasonably expected that the expanded method would allow improved production.
As recited in claim 7, the first temperature as set forth by Hanak is 37C (see figure above). The pH is about 7.0 [[0030]]. The figure also demonstrates that there is a third culture media prior to the transfection as recited in claim 30. While the diagram is limited to 24 hours for the first culture, the text states that this can be 5 hours [[0031]] as recited in claim 37. The second period of time is listed as 72 hours as recited in claim 41.
Host cells such as HEK293as recited in claim 48 is shown by Kyostio-Moore [[0109]]. As well, Kyostio-Moore teaches purification wherein the formulation is used pharmaceutically [[0122 and -0135]]. The method uses cationic polymers for transfection as recited in claim 58
Hanak teaches use of plasmid vectors carrying rep, cap and helper sequences as recited in claims 49 and 56.
Kyostio-Moore teaches that in addition to PAH as already required in claim 1, an siRNA can be included [[0094]].
It is noted that the capsid sequences are optionally required and as such claim 65 simply indicates what that sequence would be if that option were selected.
Claims 2, 18, 21, 24, 27, 43 and 44 are rejected under 35 U.S.C. 103 as being unpatentable over Kyostio-Moore (WO 2022072657) in view of Hanak and Truran (US 2021/0355503) as applied to claims 1, 7, 11, 30, 37, 41, 48, 49, 56 and 65 are rejected under 35 U.S.C. 103 as being unpatentable over above, and further in view of Gillmeister et al (CN 201980052976) and Schmelas (Dissertation, 2020, pages 1-198).
Valproic acid was added to the cell culture at about 1 mM and 2 mM improving rAAV yield. Propionic acid similarly was added 2 mM and butyric acid at 4 mM (see Example 1-5).
As to use of DMSO, Schmelas teaches use of 2.5% in the first culture media and led to enhanced expression levels as well as transduction (see supplementary Figure 3, page 177).
Based on such teachings, it would have prima facie been obvious to one of ordinary skill in the art at the time the invention was made to incorporate the valproic, butyric, propionic acids or DMSO given the improvements in rAAV production and expression. Such a modification would have resulted in a method encompassed by claims 2, 18, 21, 24, 27, 43 and 44. As noted above: 1) Kyostio-Moore teaches rAAV for therapeutic purposes; 2) Hanak and Truran teach manufacture methods for therapeutic rAAV 3) Gillmeister et al teach addition of valproic, propionic and butyric acids improve yield while 4) Schlemas teaches that DMSO improves transduction and expression from rAAV. Thus, a person of ordinary skill in the art, absent evidence to the contrary, would have reasonably expected that the expanded method would allow improved yields and expression.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARIA MARVICH whose telephone number is (571)272-0774. The examiner can normally be reached 8 am - 5 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Maria Leavitt can be reached at 571-272-1085. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/MARIA MARVICH/Primary Examiner, Art Unit 1634
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