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 .
Claim Status
Claims 1-14 are pending.
Claims 1-14 are under examination.
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 5 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 5 recites the limitations "the volume " and “the aliquot”. There is insufficient antecedent basis for these limitation in the claim. Claim 5 is dependent on Claim 1 step b which does not recite those limitations previously. Therefore, the claim is indefinite.
Claim Rejections - 35 USC § 102
(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 1-3, 5-13 are rejected under 35 U.S.C. 102(2) as being anticipated by WO 2021/146591 A2, Smith et al., 2021.
Regarding claim 1, Smith teaches a method for producing recombinant AAV (rAAV) in a host cell line (summary, page 2). The method comprising:
In certain embodiments, culturing a human embryonic cell line (summary, page 2, claims 1) which is the human embryonic kidney cell line (claim3) to a predetermined cell density of 3.0 x 106 to about 1 X108 viable cells/ml (claim 26). Specification refers to "perfusion" or "perfusion culture" as continuous culture (page 15). Claim 26 of Smith teaches culturing human embryonic cells to a predetermined density which indicates continuous culture and the introduction and removal of culture media. Also example 1 of smith teaches that the cell expansion process continued in a bioreactor prior to transfection (line 20, page 67). Therefore, Smith reads on perfusion and teach the requisite limitations of instant claim 1, step a.
Smith teaches progressively culturing the human embryonic cell suspension in increasing volumes prior to transfection (claim 19), wherein increasing volumes are progressively increased from 50ml to 2000L (claim 20). Therefore, claims 19-20 of Smith read on dilution of the first culture and addition of fresh cultivation medium to obtain a second pre-determined cell density.
Smith teaches culturing human embryonic cells 12- 36 hrs. prior to transfection (claim 31, embodiment 64, page 50).
Smith teaches transfecting the cultured human embryonic cell line (claim 1) in suspension media with nucleic acids encoding helper proteins sufficient for rAAV replication, AAV rep and cap proteins (claim1).
Smith teaches culturing the transfected cell line for at least 24 hrs. (embodiment 34, page, 47) thereby producing the rAAV (claim 1).
Regarding claim 2, Smith teaches culturing a human embryonic cell line (claims 1) to a predetermined cell density of 3.0 x 106 to about 1 X108 viable cells/ml (claim 26) which teaches the cell density 80.0 x 105 cells/ml.
Regarding claim 3, Smith teachesHEK293T and Chinese hamster ovary (CHO) K1 lineage (line 30, page 30) as suitable host cells for the AAV production.
Regarding claim 5, Smith teaches adding progressively increasing volumes of culture media from 50ml to 2000L (claim 20) to culture composition (see rejection 112b).
Regarding claim 6, Smith teaches pre-determined cell density to be 2.0 x 104 - 1.0 x 108 in some embodiments (line 15, page 19).
Regarding claim 7, Smith teaches culturing human embryonic cells 12- 36 hrs. prior to transfection (claim 31, embodiment 64, page 50) which teaches the requisite 24 hrs. culturing,
Regarding claim 8, Smith teaches cultivating cells for approximately 72hrs, post transfection (example 1, line 10, page 67).
Regarding claim 9, Smith teaches transfecting HEK293 cells in serum-free media (example 1, line 5, page 66), indicating “without feeding”.
Regarding claim 10, Smith teaches harvesting the transfected cells and purifying the rAAV vector particles (claim 34). Smith also teaches lysis of host cells (page 40, line 25-30) and isolation or separation of rAAV (line, 15, page 44).
Regarding claim 11, Smith teaches cell density at transfection to be 1 x 105 to 1 X107, in certain embodiments ( lines 10-15, page 19).
Regarding claim 12, Smith teaches increasing volume of culture medium prior to transfection( claim 44) and the transfection composition comprising 5-20% (v/v) culture media (claim 87).
Regarding claim 13, Smith teaches transfecting cells by adding nucleic acids as a mixture of PEI complexed with nucleic acid and free PEI (claims 5, 62-63).
Therefore, the reference 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 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.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over WO 2021/146591 A2, Smith et al., 2021 and in view of Choi et al., 2014.
The teachings of Smith is as relied on above on 35 U.S.C. 102 above.
Regarding claim 4, Smith further teaches transfecting human embryonic cells with nucleic acid sequences encoding; (i) helper proteins sufficient for rAAV replication, (ii) AAV rep and AAV cap,(iii) at least one ITR sequence, and (iv) heterologous transgene operably linked to regulatory elements (claim 1) or a promoter (page 21, line 30). Example 1 of Smith teaches transfecting HEK293 cells with a construct comprising, a therapeutic transgene with two ITRs flanking the 5’ to 3’, gene of interest (page 66). Helper AAV proteins are E1A, E1b55K, E2A,E4orf6 and AV genes (line 15, page 61). Also, Example 1 of Smith teaches therapeutic transgene cassettes comprising CYP and GAA transgenes.
Smith does not teach a poly adenylation signal sequence.
However, before the effective filling date of the claimed invention, inclusion polyadenylation signal in expression cassettes/nucleic acid sequences was known in the art.
Choi teaches that an AAV vector carrying polyadenylation signal (fig 1a, page 3), and teaches that polyadenylation signal increase the transgene expression(discussion, page 8).
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filling date of the claimed invention to combine the above-mentioned teachings of Smith and Choi to develop a rAAV construct, as taught by Smith, additionalycomprising a polyadenylation signal, as taught by Choi. One of ordinary skill in the art would have been motivated to combine the teachings of Smith and Choi to include a polyadenylation signal in a rAAV construct to increase the expression of a therapeutic transgene, as taught by Choi. There would be a reasonable expectation of success to combine the teachings of Smith and Choi, because they both teach optimized rAAV particles.
Hence, the claimed invention as a whole was prima facie obvious.
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over WO 2021/146591 A2, Smith et al., 2021 and Choi et al., 2014, and further in view of WO2018/226887 A1, Qu et al., 2018.
Teachings of Smith and Choi are as relied above.
Smith and Choi do not teach transfection of cells in the presence of valproic acid.
However, before the effective filling date of the claimed invention, transfection of cells in the presence of valproic acid was known in the art.
Regarding claim 14, Qu teaches production of rAAV with PEI mediated transfection in the presence of valproic acid (claim 3 c), at 5mM concentration (claim 97, fig.8, page 8). Valproic acid acts as an enhancing agent (claim14) to improve transfection efficiency (title, description)
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filling date of the claimed invention to combine the above-mentioned teachings of Smith, Choi and Qu to develop a rAAV construct and transfect the cells in the presence of 5mM valproic acid. One of ordinary skill in the art would have been motivated to combine the teachings of Smith and Choi and Qu to perform the transfection in the presence of valproic acid to improve the transfection efficiency. There would be a reasonable expectation of success to combine the teachings of Smith and Choi and Qu, because they the all teach rAAV particles optimizes to produce transgenes and both Smith and Qu teach PEI based transfection.
Hence, the claimed invention as a whole was prima facie obvious.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to HASHANTHI ABEYRATNE-PERERA whose telephone number is (571)272-6562. The examiner can normally be reached Monday-Friday 7:30 am- 5:00pm.
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, Peter Paras can be reached at 571-272-4517. 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.
/HASHANTHI KOMITIGE ABEYRATNE-PERERA/Examiner, Art Unit 1632
/MARCIA S NOBLE/Primary Examiner, Art Unit 1632
Prosecution Insights