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 .
Election/Restrictions
Applicant’s election without traverse of Group I, claims 105-127, in the reply filed on 05/08/2026 is acknowledged.
Applicant has canceled claims 128-129 which were drawn to the non-elected Group II.
Status of the Claims
Claims 105-127 are currently pending.
Claims 118, 121, and 123 are amended.
Claims 1-104 and 128-129 are cancelled.
Claims 105-127 have been considered on the merits.
Claim Rejections - 35 USC § 112(b)
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 105-127 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.
Claims 105, 108, and 110 contains the trademark/trade name FectoVIR®-AAV. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a polyethyleneimine (PEI-) based transfection reagent and, accordingly, the identification/description is indefinite. Dependent claims 106-127 are included in this rejection due to dependency on claim 105.
Claim 127 contains the trademark/trade name Expi293F™ cells. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe suspension-adapted human embryonic kidney (HEK293) cell line and, accordingly, the identification/description is indefinite.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 110 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 110 requires “wherein the transfection complex comprises a ratio of FectoVIR®-AAV to nucleic acid of 1:0-1:2”. Claim 110 depends from claim 105 and claim 105 requires “contacting the plurality of mammalian cells with a transfection complex comprising: i) FectoVIR®-AAV transfection reagent, and ii) a nucleic acid encoding a transgene and sufficient LTR sequence for packaging into a viral particle”. Thus, Claim 105 requires that both the FectoVIR®-AAV and nucleic acid be present. Claim 110 is broader than the independent claim 105 because it allows a ratio of 1:0 which implies that there would not be any nucleic acid added. Thus, claim 110 fails to further limit claim 105.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(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 105-114, 117-122, and 125-127 are rejected under 35 U.S.C. 102(a)(1)/102(a)(2) as being anticipated by Deb et al (US20180363002A1).
Claim Interpretation: Claim 105 recites a trademark in the claim which has been addressed under 35 U.S.C. 112(b). The tradename FectoVIR®-AAV is used to identify/describe a polyethyleneimine (PEI-) based transfection reagent and, accordingly, the claim limitation of “FectoVIR®-AAV” is being interpreted to be met by any PEI based transfection reagent of the art. In the case of the rejection presented below, the gold standard PEI-based transfection reagent PEIpro® is being interpreted to meet the limitation of “FectoVIR®-AAV”.
Regarding claim 105, Deb teaches a method of manufacturing lentiviral particles comprising the steps of: a) culturing a plurality of mammalian cells, Expi293F™ cells, which do not express a large T antigen, at a first pH ([0090]), b) contacting the plurality of mammalian cells with a transfection complex comprising PEIpro® transfection reagent ([0090]) and a nucleic acid encoding a transgene and sufficient LTR sequence for packaging into a viral, c) culturing the plurality of mammalian cells under conditions suitable for production of the lentiviral particles ([0089]-[0090]), d) harvesting the lentiviral particles ([0090]-[0092]), and e) purifying the lentiviral particles to produce a filtrate ([0092]).
Regarding claim 106, Deb teaches that the transfection complex comprises one or more nucleic acids encoding a lentiviral (a subset of retroviral viruses) envelope ([0006]) and a lentiviral packaging protein ([0044]).
Regarding claim 107, Deb teaches that the transgene encodes a CAR comprising an antigen binding domain, a transmembrane domain, and one or more signaling domains ([0085]).
Regarding claim 108, Deb teaches that the transfection complex comprises PEIpro® at an overall concentration of about 0.4-0.5 µL per 1 million cells. This concentration was found through the following reasoning: 12.5 ml of PEIpro® was added to 0.25 liters of medium and combined with 0.25 liters of medium containing the nucleic acids for a total of 0.5 liters, half (0.25 liters) of the PEIpro® /nucleic acid mixture was added to 2.25 liters of medium to achieve an overall 2.5 liters of media with a cell concentration of 5-6x106 cells/ml which would amount to a final concentration of about 0.4-0.5 µL of PEIpro® per 1 million cells.
Regarding claim 109, Deb teaches that the transfection complex comprises the nucleic acid at an overall concentration of about 0.4-0.5 µL per 1 million cells. This concentration was found through the following reasoning: 12.8 mg of nucleic acid plasmid was added to 0.25 liters of medium and combined with 0.25 liters of medium containing the PEIpro® for a total of 0.5 liters, half (0.25 liters) of the PEIpro® /nucleic acid mixture was added to 2.25 liters of medium to achieve an overall 2.5 liters of media with a cell concentration of 5-6x106 cells/ml which would amount to a final concentration of about 0.4-0.5 µg of nucleic acid per 1 million cells.
Regarding claim 110, the ratio of PEIpro® to nucleic acids is about 1:1 as demonstrated by the addition of 12.5 ml of PEIpro® and 12.8 mg of nucleic acid plasmids which have been demonstrated to be about 0.4-0.5 µL of PEIpro® to 0.4-0.5 µg of nucleic acid plasmid in the discussions regarding claims 108-109 above ([0090]).
Regarding claim 111, Deb teaches that the freestyle medium used was lowered to a pH of about 6 before contacting with cells ([0090]).
Regarding claim 112, the Freestyle medium is known to have a pH of about 7 and Deb adjusted the pH of the freestyle medium to about 6 pH units which meets the limitation of the second pH being between 0.1-1.0 units lower ([0090]).
Regarding claim 113-114, Deb teaches that a nuclease of Benzonase is added prior to step d of claim 105 ([0026]/[0092]).
Regarding claim 117, Deb teaches wherein the solution further comprises a buffer, salt, ([0010]) a non-reducing carbohydrate ([0012]), and a pH of about 6-7 ([0090]).
Regarding claim 118, Deb teaches that the buffer is PIPES at a concentration of 10-50 mM ([0011]).
Regarding claim 119, Deb teaches that the salt is at a concentration of 25-150 mM ([0011]).
Regarding claim 120, Deb teaches that the salt is sodium chloride, magnesium chloride, and calcium chloride ([0011]).
Regarding claim 121, Deb teaches that the non-reducing carbohydrate is present in the solution at about 1-10% ([0012]).
Regarding claim 122, Deb teaches that the non-reducing carbohydrate is selected from sucrose and trehalose ([0012]).
Regarding claim 125, Deb teaches that the method yields at least 1x107 lentiviral particles ([0094]).
Regarding claim 126, Deb teaches that the filtrate has a reduced aggregation of the lentiviral particles ([0045]/[0079]/Fig. 1).
Regarding claim 127, Deb teaches that the mammalian cells are Expi293F cells ([0090]).
Thus, Deb anticipates the claims.
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 105-114, 117-122, and 125-127 are rejected under 35 U.S.C. 103 as being unpatentable over Deb et al (US20180363002A1), in view of Nyamay’antu et al (Cell and Gene Therapy Insights, 2020).
Regarding claim 105, Deb teaches a method of manufacturing lentiviral particles comprising the steps of: a) culturing a plurality of mammalian cells, Expi293F™ cells, which do not express a large T antigen, at a first pH ([0090]), b) contacting the plurality of mammalian cells with a transfection complex comprising PEIpro® transfection reagent ([0090]) and a nucleic acid encoding a transgene and sufficient LTR sequence for packaging into a viral, c) culturing the plurality of mammalian cells under conditions suitable for production of the lentiviral particles ([0089]-[0090]), d) harvesting the lentiviral particles ([0090]-[0092]), and e) purifying the lentiviral particles to produce a filtrate ([0092]).
Regarding claim 106, Deb teaches that the transfection complex comprises one or more nucleic acids encoding a lentiviral (a subset of retroviral viruses) envelope ([0006]) and a lentiviral packaging protein ([0044]).
Regarding claim 107, Deb teaches that the transgene encodes a CAR comprising an antigen binding domain, a transmembrane domain, and one or more signaling domains ([0085]).
Regarding claim 108, Deb teaches that the transfection complex comprises PEIpro® at an overall concentration of about 0.4-0.5 µL per 1 million cells. This concentration was found through the following reasoning: 12.5 ml of PEIpro® was added to 0.25 liters of medium and combined with 0.25 liters of medium containing the nucleic acids for a total of 0.5 liters, half (0.25 liters) of the PEIpro® /nucleic acid mixture was added to 2.25 liters of medium to achieve an overall 2.5 liters of media with a cell concentration of 5-6x106 cells/ml which would amount to a final concentration of about 0.4-0.5 µL of PEIpro® per 1 million cells.
Regarding claim 109, Deb teaches that the transfection complex comprises the nucleic acid at an overall concentration of about 0.4-0.5 µL per 1 million cells. This concentration was found through the following reasoning: 12.8 mg of nucleic acid plasmid was added to 0.25 liters of medium and combined with 0.25 liters of medium containing the PEIpro® for a total of 0.5 liters, half (0.25 liters) of the PEIpro® /nucleic acid mixture was added to 2.25 liters of medium to achieve an overall 2.5 liters of media with a cell concentration of 5-6x106 cells/ml which would amount to a final concentration of about 0.4-0.5 µg of nucleic acid per 1 million cells.
Regarding claim 110, the ratio of PEIpro® to nucleic acids is about 1:1 as demonstrated by the addition of 12.5 ml of PEIpro® and 12.8 mg of nucleic acid plasmids which have been demonstrated to be about 0.4-0.5 µL of PEIpro® to 0.4-0.5 µg of nucleic acid plasmid in the discussions regarding claims 108-109 above ([0090]).
Regarding claim 111, Deb teaches that the freestyle medium used was lowered to a pH of about 6 before contacting with cells ([0090]).
Regarding claim 112, the Freestyle medium is known to have a pH of about 7 and Deb adjusted the pH of the freestyle medium to about 6 pH units which meets the limitation of the second pH being between 0.1-1.0 units lower ([0090]).
Regarding claim 113-114, Deb teaches that a nuclease of Benzonase is added prior to step d of claim 105 ([0026]/[0092]).
Regarding claim 117, Deb teaches wherein the solution further comprises a buffer, salt, ([0010]) a non-reducing carbohydrate ([0012]), and a pH of about 6-7 ([0090]).
Regarding claim 118, Deb teaches that the buffer is PIPES at a concentration of 10-50 mM ([0011]).
Regarding claim 119, Deb teaches that the salt is at a concentration of 25-150 mM ([0011]).
Regarding claim 120, Deb teaches that the salt is sodium chloride, magnesium chloride, and calcium chloride ([0011]).
Regarding claim 121, Deb teaches that the non-reducing carbohydrate is present in the solution at about 1-10% ([0012]).
Regarding claim 122, Deb teaches that the non-reducing carbohydrate is selected from sucrose and trehalose ([0012]).
Regarding claim 125, Deb teaches that the method yields at least 1x107 lentiviral particles ([0094]).
Regarding claim 126, Deb teaches that the filtrate has a reduced aggregation of the lentiviral particles ([0045]/[0079]/Fig. 1).
Regarding claim 127, Deb teaches that the mammalian cells are Expi293F cells ([0090]).
Although Deb does teach the use of PEIpro® in the method of [0090], Deb does not teach that the PEI based transfection reagent is FectoVIR®-AAV as required by claims 105, 108, and 110.
However, Nyamay’antu teaches about FectoVIR®-AAV and PEIpro® (abstract and Fig. 1). Nyamay’antu teaches that “PEI pro® transfection reagent is a highly qualified PEI that has become the gold standard for large-scale production of viral vectors such as adenovirus, lentivirus and AAVs both in adherent and suspension systems” (pg. 657, col. 1, para 2). Nyamay’antu teaches that when transfecting HEK293T cells using FectoVIR®-AAV results in a 2x fold increase in functional titers than the gold standard PEIpro® (Fig. 1).
One of ordinary skill in the art would find it obvious at the effective filling date of the instant invention to combine the method of manufacturing lentiviral particles taught by Deb with the VectoVIR®-AAV transfection reagent taught by Nyamay’antu to arrive at the instant invention. One of ordinary skill in the art would be motivated to make this combination because Nyamay’antu teaches that when transfecting HEK293T cells using FectoVIR®-AAV results in a 2x fold increase in functional titers than the gold standard PEIpro® (Fig. 1). One of ordinary skill in the art would have a reasonable expectation of success when combining Deb with Nyamay’antu because Deb teaches the use of a PEI-based transfection reagent and Nyamay’antu teaches that “PEI pro® transfection reagent is a highly qualified PEI that has become the gold standard for large-scale production of viral vectors such as adenovirus, lentivirus and AAVs both in adherent and suspension systems” (pg. 657, col. 1, para 2) and that the VectoVIR®-AAV results in a 2x fold increase in functional titers in HEK293T cells which are a less specialized form of the HEK293 cells used in Deb, Expi293F cells.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Claim(s) 105, 115-116, and 123-124 are rejected under 35 U.S.C. 103 as being unpatentable over Deb et al (US20180363002A1), in view of Nyamay’antu et al (Cell and Gene Therapy Insights, 2020, applied to claims 105-114, 117-122, and 125-127 above, and in further view of Rodriguez et al (Acta Biomaterialia, 2016).
With regards to claims 115-116 and 123-124, the limitations of the independent claim 105 are taught above.
Deb teaches the use of the Freestyle medium from Life Technologies throughout the method as demonstrated in ([0090]). The Freestyle medium is a proprietary medium and the exact contents are not readily available, however it appears it is highly possible that the Freestyle medium may contain arginine at some concentration which is not disclosed due to common inclusion of L-arginine in basic cell culture media.
However, Rodriguez teaches about the use of buffers containing arginine for enhanced assembly and colloidal stabilization of virus like particles, and more specifically viral capsid formation (abstract). Rodriguez teaches that their results demonstrate that arginine improves the protein solubility of virus like particles and that this suppression of protein aggregation may be due to cation-pi interactions (pg. 213, col. 1, para 2).
With regards to claims 115-116 and 123-124, Rodriguez teaches the inclusion of between 0.05-0.4 M, or 50-400 mM, of arginine in PBS (pg. 207, col. 2, para 3).
One of ordinary skill in the art would find it obvious at the effective filling date of the instant invention to combine the method of manufacturing lentiviral particles taught by Deb and Nyamay’antu with the arginine supplementation taught by Rodriguez to arrive at the instant invention. One of ordinary skill in the art would be motivated to make this combination because Rodriguez teaches that their results demonstrate that arginine improves the protein solubility of virus like particles and that this suppression of protein aggregation may be due to cation-pi interactions (pg. 213, col. 1, para 2). One of ordinary skill in the art would have a reasonable expectation of success when combining Deb and Nyamay’antu because Deb and Nyamay’antu teach the necessary information to carry out the claimed method Rodriguez teaches that inclusion of arginine results in improved protein stability and suppression of protein aggregation.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, 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 CONSTANTINA E STAVROU whose telephone number is (571)272-9899. The examiner can normally be reached M-F 8:00-5:00.
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CONSTANTINA E. STAVROU
Examiner
Art Unit 1632
/ANOOP K SINGH/Primary Examiner, Art Unit 1632
Prosecution Insights