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 .
Priority
The instant application is a national stage entry under 35 USC 371 of PCT/EP2021/061673 (filed on 05/04/2021), which claims priority to EP application 20172806.0 (filed on 05/04/2020).
Claims Status
A preliminary amendment was received on 11/04/2022. Claims 1-16 are pending, all of which have been considered on the merits.
Claim Objections
Claim 1 is objected to because of the following informalities:
A claim should consist of a single sentence, starting with a capital letter and ending with a period. Periods should not be used elsewhere in the claim (except for abbreviations). See MPEP 608.01(m). Claim 1 uses multiple periods. It would be remedial to change “a.”, “b.”, etc. to “a)”, “b)”, etc.” .
Claims 2-16 are objected to because of the following informalities:
The claims should begin with 'The' not 'A' .
Claims 2 and 11 are objected to because of the following informalities:
Claim 2 has a grammatical error, "further comprising the change of the medium" should read, 'further comprising changing medium".
Claim 11 has a grammatical error, it should read, ' using reservoir, and fresh medium in a total...'.
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 1-16 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as failing to set forth 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 1 recites the limitation "the cells" in line 3. There is insufficient antecedent basis for this limitation in the claim. It is unclear which cells the claim is referring to.
Claim 1 recites the limitation "the PEI transfection reagent;" in line 5. There is insufficient antecedent basis for this limitation in the claim, due to a PEI transfection reagent not having been established.
Claim 1 recites the limitation "the recombinant lentiviral vectors" in line 6. There is insufficient antecedent basis for this limitation in the claim. Line 1 of claim 1 discloses lentiviral vectors, but does not specify they are recombinant lentiviral vectors.
Claims 2-16 depend directly or indirectly from claim 1, inherit the deficiencies, and thus are rejected on the same basis.
Claim 2 recites the limitation "the medium at the end transfection" in line 2, as well as the limitation “change of medium is” also in line 2. It is unclear which step in claim 1 includes changing medium or ending of the transfection, therefore is insufficient antecedent basis for this limitation in the claim.
Claim 8 recites the limitation "the post transfection change of medium." in line 2. There is insufficient antecedent basis for this limitation, as neither parent claim 1 nor 4 describe a post transfection change of medium. Furthermore, it is unclear if the claim is requiring that the harvesting lasts for 39 hours or will occur 39 hours post transfection. Clarification is required.
Claim 16 recites the limitation "the gene encoding the envelope protein" in line 3, “the transfer vector” in line 4, and “the foreign gene of interest” in line 5. There is insufficient antecedent basis for these limitations in the claim, due to the aforementioned limitations not being established.
Claim 16 recites “multi-plasmid DNA is composed of” in line 2. This does not make sense, and renders the claim indefinite. It appears the claim should read, “comprised of”.
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.
Claims 1-16 are rejected under 35 U.S.C. 103 as being unpatentable over McCarron et al. (Human gene therapy methods, 2019).
McCarron et al teaches a method of producing LVV within a packed bed bioreactor. Specifically, McCarron et al teaches seeding a packed bed bioreactor (See, p94), operated in batch mode (See, p94), with HEK293T cells (See, p94) and culturing the cells for 3 days (See, p94), then transiently transfecting the cells with a multi-plasmid with PEI agent (See, p94), a total medium replacement 8 hours post transfection (See, p95), and finally harvesting the cell culture supernatant 48 and 72 hours post transfection (See, p95). The transfection in McCarron et al is done with a DNA:PEI ratio of 1:3 and 4.77mg DNA and 14.31mg PEI respectively. The BioBLU bioreactor in McCarron et al is 18 m2 (See, p94), which with the concentration of DNA at 4.77mg (See, p95), equates the concentration of DNA in the 4.77mg/18m2 = 26.5 ng/ cm2. The multi-plasmid used in the teaching of McCarron et al consists of Rev, GagPol, Tat, VSV-G, and a GFP transfer vector (See, p94).
Regarding claim 1, McCarron et al. teaches a method for manufacturing of lentiviral vectors in a packed bed bioreactor. The method comprises of inoculating cells to the bioreactor and allowing for cell culturing for 3 days, transfecting the cells with a multi-plasmid combined with PEI reagent, and harvesting recombinant LVVs. The method of McCarron et al reads on steps a, b, and d and is comparable to step c of the claim.
The method of McCarron et al differs from the instant claims in that McCarron et al teaches the use of total DNA at 26.5 ng/cm2 and the claim limitation is 45ng/cm2 to 100ng/cm2. McCarron et al teaches experimental optimization of the transfection conditions, including assessing plasmid quantities, DNA quantities and ratio with PEI (See, p99, col 2).
Therefore, McCarron et al. provides explicit motivations to optimize the DNA concentration for the transfection to achieve desired LVV manufacturing, and illustrates that such optimization would have been a matter of routine experimentation. Thus, it would have been obvious to one of the skills in the art prior to the effective filing date to optimize the total DNA to achieve LLV manufacturing.
In this care of a result effective variable, the discovery of an optimum value of the variable in a known proves is ordinarily within the skill of the art. Where the general conditions of the claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. Therefore, it would have been obvious to one of ordinary skill in the art to determine through routine experimentation the optimum or workable ranges of parameters such as increasing DNA concentration or cell seeding concentration since the variables would have been recognized as result-effective (See, MPEP 2144.05)
Regarding Claim 2, following the discussion of claim 1 above, McCarron et al. teaches the method of changing the medium from the bioreactor on batch mode at the end of transfection. This reads on the limitations set forth by claim 2.
Regarding claim 3, following the discussion of claim 2 above, McCarron et al teaches a method of changing the medium in batch mode at 48 hours post transfection with a complete supernatant harvest, this reads on draining the bioreactor of cell culture medium and a transfer of new medium for continued culturing, reads on adding fresh medium to the cell culture (See, p95).
Regarding claims 4 and 5, following the discussion of claim 1 above, McCarron et al teaches that perfusion mode can be used during the run to improve cell viability and density. McCarron et al also teaches that perfusion mode will allow the full surface area of the packed-bed to be exploited, thereby increasing the overall productivity of the system (See, p99, col. 2). Therefore, it would have been obvious to have modified the method of McCarron et al to use perfusion mode to harvest the cell culture supernatant, this reads on the limitation wherein harvesting of the cell culture supernatant is performed in perfusion mode of claim 4. One would have been motivated to use perfusion mode because McCarron teaches that use of perfusion mode with the bioreactor can increase cell viability and density. One would have had a reasonable expectation of success because McCarron et al teaches this is an optimization on the taught method and it is method used within the art. The limitation of claim 5 includes those from claims 1 and 3, it is included in the rejections stated above and is read on by the motivation set forth by McCarron et al to complete the method in perfusion mode, which includes harvesting the LVVs from the bioreactor.
Regarding claim 6, following the discussion of claim 1 above, McCarron et al teaches the cells are transfected for 8 hours (See, p95), which clearly reads on the limitation wherein the cells are transfected for a period of up to 18 hours.
Regarding claims 7 and 8, following the discussion of claim 4 above, McCarron et al renders obvious harvesting the LVVs from the bioreactor using perfusion mode. McCarron et al teaches harvesting the LVVs at 48 and 72 hrs post transfection (See, p95).
It would have been prima facie obvious to have continually harvested the LVVs using perfusion mode for a period of time up to an including 48 hrs, as McCarron et al shows that the cells were producing LVVs up to the 48 hr mark. This renders obvious the limitation set by claim 7, harvesting in perfusion mode is performed for at least 39 hours post transfection. The limitation set by claim 8, harvesting in perfusion mode is performed for 39 hours after the post transfection change of medium, is an optimization of the method of harvesting at 48 hours.
In this care of a result effective variable, the discovery of an optimum value of the variable in a known proves is ordinarily within the skill of the art. Where the general conditions of the claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. Therefore, it would have been obvious to one of ordinary skill in the art to determine through routine experimentation the optimum or workable ranges of parameters such as varying the time and mode used by the bioreactor, since the variables would have been recognized as result-effective (See, MPEP 2144.05).
Regarding claim 9, claim 9 is interpreted as a removal of medium between cell culturing and transfection. Official notice is taken then when doing transfection step it is standard in the art to either remove the culture medium and replace with transfection medium that includes the DNA and PEI or adding the transfection medium directly to the culture, both techniques yield the same result: exposure of the cells to the transfection reagent. It would have been at least obvious to try to completely change the culture medium to transfection medium in the method of McCarron et al because this was one of the well-known techniques for applying transfection reagent to cells. It has been held that "a person with ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense." See KSR International Co. v Teleflex, Inc. 82 USPQ2d 1385 at 1390.
Regarding claims 10 and 11, following the discussion of claim 4 above, McCarron et al renders obvious that the method can be used in perfusion mode and the culture cells are in the bioreactor (18m2) in 3.75 L medium, which equates to 0.021 ml/cm2. This is comparable to the limitations set by the claims of 0.1 ml/cm2. McCarron et al teaches experimental optimization of the transfection conditions, including use of perfusion mode and transfection conditions (See, p99).
Therefore, McCarron et al. provides explicit motivations to optimize the expansion of the cultivated cells and perfusion mode, which includes recirculation of medium, to achieve desired LVV manufacturing, and illustrates that such optimization would have been a matter of routine experimentation. Thus, it would have been obvious to one of the skills in the art prior to the effective filing date to optimize the cell culturing conditions for transfection to achieve LLV manufacturing.
In this care of a result effective variable, the discovery of an optimum value of the variable in a known proves is ordinarily within the skill of the art. Where the general conditions of the claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. Therefore, it would have been obvious to one of ordinary skill in the art to determine through routine experimentation the optimum or workable ranges of parameters such as the use of mode for the bioreactor or the amount of medium since the variables would have been recognized as result-effective (See, MPEP 2144.05).
Regarding claim 12, following the above discussion, the transfection step taught by McCarron et al. does not involve perfusion or recirculation of fresh medium and this reads on transfection step (c) is performed in the absence of perfusion or recirculation of fresh medium of claim 12.
Regarding claim 13, following the discussion of claim 1 above, McCarron et al teaches that the transfection in the method is done with a DNA:PEI ratio of 1:3, which is comparable to the DNA:PEI ratio of 1:1 of the claim. McCarron et al teaches experimental optimization of the transfection conditions, including assessing plasmid quantities, DNA quantities and ratio with PEI (See, p99).
Therefore, McCarron et al. provides explicit motivations to optimize the ratio of DNA and PEI for transfection to achieve desired LVV manufacturing, and illustrates that such optimization would have been a matter of routine experimentation. Thus, it would have been obvious to one of the skills in the art prior to the effective filing date to optimize the transfection conditions to achieve LLV manufacturing.
In this care of a result effective variable, the discovery of an optimum value of the variable in a known proves is ordinarily within the skill of the art. Where the general conditions of the claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. Therefore, it would have been obvious to one of ordinary skill in the art to determine through routine experimentation the optimum or workable ranges of parameters such as increasing DNA concentration or PEI concentration since the variables would have been recognized as result-effective (See, MPEP 2144.05)
Regarding claim 14, following the discussion of claim 1 above, McCarron et al teaches that the medium is changed 8 hours post transfection, which indicates that the cells are transfected for 8 hours. This reads on the limitation of claim 14, wherein the cells are transfected under step (c) for a period of 8 hours.
Regarding claim 15, following the discussion of claim 1 above, McCarron et al teaches the method of manufacturing LVVs with HEK293T cells, which clearly reads on the use of HEK293T cells in claim 15.
Regarding claim 16, following the discussion of claim 1 above, McCarron et al teaches multi-plasmid used in the method consists of Rev, GagPol, Tat, VSV-G envelope plasmid, and a GFP transfer vector, with HIV-1 for the purposes of McCarron et al studies. (See, p94), which clearly reads on multi-plasmid DNA composed by one plasmid carrying the lentiviral gag/pol genes, one plasmid carrying lentiviral rev gene, one plasmid carrying the gene encoding the envelope protein, and one plasmid carrying the transfer vector including the required portion of the lentiviral genome and the foreign gene of interest.
Therefore, the methods of claims 1-16 are rejected over McCarron et al.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Caroline M Lara whose telephone number is (571)272-4262. The examiner can normally be reached 7:00 to 3:00pm M-F.
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/CAROLINE M LARA/Examiner, Art Unit 1633
/ALLISON M FOX/Primary Examiner, Art Unit 1633