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 .
The preliminary amendment filed on 07/10/2023 has been entered.
Claims 53-72 are pending in the present application, and they are examined on the merits herein.
Claim Objections
Claim 53 is objected to because of the term “SPTFF”, which should be spelled out in full at the first occurrence of the term.
Similarly, claim 58 is also objected to because of the term “MWCO”, which should be spelled out in full at the first occurrence of the term.
Claim Rejections - 35 USC § 112
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.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
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 of carrying out his invention.
Claim 63 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for:
A method of purifying a viral vector composition comprising the steps of:
(a) feeding a composition comprising a viral vector through an SPTFF system, the system comprising: (i) a feed pump; and (ii) one or more SPTFF filtration modules, wherein the SPTFF filtration modules purify the viral vector composition; and
(b) collecting a purified viral vector composition,
wherein the SPTFF filtration module has an average transmembrane pressure (TMP) of at least 3 psi;
does not reasonably provide enablement for a method of purifying a viral vector composition in which the SPTFF filtration module has an average transmembrane pressure (TMP) lower than 3 psi. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
The factors to be considered in the determination of an enabling disclosure have been summarized as the quantity of experimentation necessary, the amount of direction or guidance presented, the state of the prior art, the relative skill of those in the art, the predictability or unpredictability of the art and the breadth of the claims. Ex parte Forman, (230 USPQ 546 (Bd Pat. Appl & Unt, 1986); In re Wands, 858 F.2d 731, 8 USPQ 2d 1400 (Fed. Cir. 1988)).
The instant specification is not enabled for the instant broadly claimed invention for the reasons discussed below.
1. The breadth of the claims
The instant claim encompasses a method of purifying a viral vector composition comprising the steps of: (a) feeding a composition comprising a viral vector through an SPTFF system, the system comprising: (i) a feed pump; and (ii) one or more SPTFF filtration modules, wherein the SPTFF filtration modules purify the viral vector composition; and (b) collecting a purified viral vector composition, wherein the SPTFF filtration module has an average transmembrane pressure (TMP) of about 5 psi or lower (e.g., 4 psi, 3 psi, 2 psi, 1 psi, or 0.5 psi).
2. The state and the unpredictability of the prior art
Before the effective filing date of the present application (03/18/2016), virtually nothing was known about a method of purifying a viral vector composition using a Single Pass Flow Filtration (SPFF) system, in which a SPTFF filtration module has an average transmembrane pressure (TMP) of about 5 psi or lower as evidenced at least by the teachings of Dizon-Maspat et al (Biotechnology and Bioengineering 109:962-970, 2011), Arunkumar et al (WO 2019/236811; IDS), Gefroh et al (US 2017/0157566; IDS), Hong et al (US 12,018,293) and Qu et al (WO 2014/145578; IDS). It is noted that an average TMP can be calculated by dividing the sum of the feed pressure entering into an SPTFF filtration module and the retentate pressure exiting the SPTFF filtration module by two; and substracting the permeate pressure. TMP = [(feed pressure + retentate pressure)/2] – permeate pressure (page 34, lines 5-10).
3. The amount of direction or guidance provided
Apart from stating “Despite manufacturer recommendations to operate at higher flow rates to maximize transmembrane pressure and improve concentration factors, Table 1 shows that, surprisingly, volumetric concentration factors increased with slower flow rates and product concentration factors increased along with it, up to a certain point”, and Table 1 shows the lowest operated TMP is 3.08 psi (Example 3 and Table 1); the instant specification failed to provide sufficient guidance for an ordinary skilled artisan on how to make and use an SPTFF system in which a SPTFF filtration module has an average TMP lower than 3 psi, and yet the SPTFF system still results in purifying a viral vector composition as encompassed broadly by the instant claim. There is no evidence of record indicating or suggesting in the present application or in the prior art in which an SPTFF system comprising a SPTFF filtration module with an average TMP lower than 3 psi (e.g., 2 psi, 1 psi, or 0.5 psi) could result in a purification of a viral vector composition. Since the prior art before the effective filing date of the present application failed to provide sufficient guidance regarding to the aforementioned issue, it is incumbent upon the present application to do so. Given the state of the prior art, coupled with the lack of sufficient guidance provided by the present application, it would have required undue experimentation for a skilled artisan to make and use the instant invention as claimed broadly.
The physiological art is already recognized as unpredictable (MPEP 2164.03). As set forth in In re Fisher, 166 USPQ 18 (CCPA 1970), compliance with 35 USC 112, first paragraph requires:
That scope of claims must bear a reasonable correlation to scope of enablement provided by specification to persons of ordinary skill in the art; in cases involving predictable factors, such as mechanical or electrical elements, a single embodiment provides broad enablement in the sense that, once imagined, other embodiments can be made without difficulty and their performance characteristics predicted by resort to known scientific laws; in cases involving unpredictable factors, such as most chemical reactions and physiological activity, scope of enablement varies inversely with degree of unpredictability of factors involved.
Moreover, the courts have also stated that reasonable correlation must exist between scope of exclusive right to patent application and scope of enablement set forth in the patent application (27 USPQ2d 1662 Ex parte Maizel.).
Accordingly, due to the lack of sufficient guidance provided by the specification regarding to the issue set forth above, the state and unpredictability of the relevant art, and the breadth of the instant claim, it would have required undue experimentation for one skilled in the art to make and use the instant broadly claimed invention.
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 62, 67 and 70 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.
In claim 62, it is unclear what is encompassed by the limitation “at least about 10x”. This is because it is unclear what is the minimal threshold level, for example 8x, 8.5x, 9x, 9.5x, 10.5x, or 11x. Clarification is requested because the metes and bounds of the claim are not clearly determined.
In claim 67, it is unclear what is encompassed by the limitation “a 0.22 μM final filter”. This is because “μM” is usually a volume unit, and not a unit for a pore size. Clarification is requested because the metes and bounds of the claim are not clearly determined.
Claim 70 contains the trademark/trade name denarase. 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 DNA endonuclease and, accordingly, the identification/description is indefinite.
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.
Claims 53-62, 64-69 and 71-72 are rejected under 35 U.S.C. 103 as being unpatentable over Dizon-Maspat et al (Biotechnology and Bioengineering 109:962-970, 2011) in view of Arunkumar et al (WO 2019/236811; IDS), Hong et al (US 12,018,293) and Qu et al (WO 2014/145578; IDS).
The instant claims encompass a method of purifying a viral vector composition comprising the steps of: (a) feeding a composition comprising a viral vector through an SPTFF system, the system comprising: (i) a feed pump; and (ii) one or more SPTFF filtration modules, wherein the SPTFF filtration modules purify the viral vector composition; and (b) collecting a purified viral vector composition.
Dizon-Maspat et al already disclosed the use of Single Pass Tangential Flow Filtration (SPTFF) to debottleneck downstream processing for therapeutic antibody production; and they found that using SPTFF to concentrate protein pools is a simple, flexible, and robust operation, which can be implemented at various scales to improve antibody purification process capacity (Abstract). Dizon-Maspat et al taught that SPTFF is a new technology which aims to concentrate protein solutions in single pass, without the need for a recirculation loop and tank; and it is designed to have multiple conventional TFF stages in a single unit, which requires minimal capital investment and footprint areas with an example is provided in Fig. 1b shown below (page 963, left column, first full paragraph; Figure 1).
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Fig. 1b shows a 5-in-series SPTFF module in which SPTFF membranes are arranged in parallel and in-series; and the module comprises the first two stages have 3 cassettes each, the next two stages have 2 cassettes each, and the final stage has one cassette, for a total of 11 cassettes. Dizon-Maspat et al also stated “With the SPTFF modules, adding more levels of membranes increases the path length and the residence time of the solution in the filter, thus a larger amount of permeate is removed and the feed volume decreases with just one pass. The membrane area is lower for later stages to compensate for the reduction in volume and maintain fluid velocity to control pressure and avoid fouling” (page 963, left column, top of third paragraph). Dizon-Maspat et al specifically evaluated two SPTFF ultrafiltration modules: the 4-in-series module (composed of 7 filtration cassettes organized in 1 group of 3 cassettes, 1 group of 2 cassettes and 2 groups of 1 cassette with a total area of 0.167 m2) and the 9-in-series module (composed of 3 groups of 3 cassettes, 3 groups of 2 cassettes and 3 groups of 1 cassette with a total area of 0.167 m2) in a test system that includes two pumps (feed and retentate), two flow meters (feed and retentate), six pressure flow cells, the SPTFF holder, and a data logger; and the operation of SPTFF modules includes the step of concentrating the protein solution and recovering the hold-up from the system (Section titled “SPTFF Ultrafiltration Modules” at page 964). Dizon-Maspat et al also tested retentate pressure in the range of 0-11 psi and 0-20 psi for the 4-in-series module and the 9-in-series module, respectively (page 965, left column, first paragraph; and Table 1). Figure 9a shows the pressure and VCF (Volumeric Concentration Factor) achieved when the 4-in-series SPTFF module was used to run mAb C in single pass, with the actual VCF was within the acceptable range of 1.6x and 3.6x, along with the feed pressure of approximately 17 psi and the acceptable retentate pressure of approximately 2 psi (page 969; left column, third paragraph; and Figure 9a). Dizon-Maspat et al also taught application for SPTFF modules in a standard mAb purification process as shown in Figure 7 below.
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Dizon-Maspat et al did not teach explicitly at least a method of purifying or concentrating a viral vector composition using the above disclosed SPTFF system, preferably the viral vector is a lentiviral vector.
Before the effective filing date of the present application (06/11/2020), Arunkumar et al already taught a method for concentrating a solution of a biological macromolecule that is retained on at least two semi-permeable membranes that have different molecular weight cutoffs (MWCOs) by passing the solution through a hybrid configuration of said semi-permeable membranes staged in series in a single pass tangential flow filtration (SPTFF) apparatus as depicted in Figure 1 shown below, wherein the final membrane in the series of membranes has a larger MWCO than the preceding membrane or membranes (e.g., the 30-30-50 kDa hybrid configuration for an antibody with MW of about 140-150 kDa), and wherein the biological macromolecule includes a protein such as an antibody; a nucleic acid, a DNA (e.g., chromosomal DNA, genomic DNA, cDNA, viral DNA, expression vector DNA, plasmid DNA, a viral vector DNA), an RNA and a virus (Abstract; Summary of the Invention; page 7, line 29 continues to line 8 at page 8; page 17, lines 10-17; and Fig. 1).
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Arunkumar et al stated “Ultrafiltration membranes are typically classified by MWCO rather than pore size, and TFF typically utilizes ultrafiltration membranes ranging from about 1 to 1000 kDa MWCOs to retain different size molecules” (page 7, lines 24-26); and “The retention characteristics of different MWCO membranes are known for different solutes such as nucleic acids, proteins, and virus particles (see, e.g., Pall Corporation Selection Guide: Separation Products for Centrifugal and Tangential Flow Filtration, available on line). For proteins, it is recommended that a MWCO be selected that is about three to about six times smaller than the molecular weight of the solute being retained” (page 18, lines 11-16). Table 2 shows MWCO selection for protein SPTFF applications with 30 kDa MWCO for a protein with a molecular mass in the range of 90-180 kDa, 50 kDa MWCO for a protein with a molecular mass in the range of 150-300 kDa, and 300 kDa MWCO for a protein with a molecular mass in the range of 900-1,800 kDa.
Additionally, Hong et al also disclosed a method for large-scale preparation of a purified preparation of a recombinant lentiviral vector at the GMP grade, and the method comprises: (a) providing raw material feed liquid to be purified that comprises recombinant viral vectors; (b) carrying out a microfiltration treatment on the feed liquid to obtain a microfiltered filtrate comprising the recombinant viral vectors; (c) optionally concentrating the filtrate to obtain a concentrated filtrate; (d) purifying the filtrate obtained in the previous step by means of chromatography to obtain a crude pure product comprising the recombinant viral vectors; and (e) subjecting the crude pure product obtained in the previous step to liquid exchange and elaborate purification to obtain the purified recombinant viral vectors; wherein the chromatography is selected from the group consisting of anion chromatography, size exclusion chromatography, multi-mode composite resin chromatography, and combinations thereof; and wherein in step (c) the concentration is performed by ultrafiltration using an ultrafiltration membrane with a cut-off value of 100-800K, preferably the cut-off value of the ultrafiltration hollow fiber column is 300-500 K (see at least Abstract; Summary of the Invention; particularly col. 3, lines 52-59).
Moreover, Qu et al already disclosed at least a scalable manufacturing process to produce recombinant lentiviral vectors in serum-free suspension cell culture system (e.g., a spinner flask cell culture) to meet anticipated demand for human gene therapy, the process comprises: a) harvesting recombinant lentiviral vectors comprising a transgene from serum free suspension culture; b) clarifying the harvest of step a) via filtration; c) subjecting the clarified suspension of step b) to tangential flow filtration to reduce volume and exchange buffer; d) harvesting the filtrate from step c) and optionally exposing said filtrate to nuclease digestion to remove DNA/RNA impurities; e) subjecting the filtrate of step d) to PEG-modulated affinity or ion exchange column chromatography, thereby isolating said lentiviral vectors; f) subjecting the lentiviral vectors of step e) to tangential flow filtration to reduce the volume and buffer exchange; f) subjecting the lentiviral vectors obtained from step e) to size exclusion column chromatography to further purify said lentiviral vectors; g) subjecting the vectors of step f) to tangential flow filtration, and thereby obtaining final lentiviral vector titer; h) filtering a lentiviral vector solution obtained from step g) through a filter; and i) collecting said purified lentiviral viral vectors (Abstract; Summary; particularly paragraphs [0010], [0102]; and Figure 1B). Qu et al also taught that the recombinant lentiviral vectors are produced by mammalian cells such as HEK 293T, HEK293F, HEK293, 293S cells (paragraph [0016]); employed nucleases include an endonuclease such as a benzonase or a DNase is used to reduce or decrease the amount of a nucleic acid impurity in harvested or a preparation of recombinant lentiviral vectors (paragraphs [0018] and [0057]); and a filter has a pore diameter of about 0.20-0.50 um, preferably filtering is through 0.20 um pore diameter filter, a 0.22 um pore diameter filer, or a 0.45 um pore diameter filter (paragraphs [0025] and [0067]). Fig. 1B is a flow chart of an exemplary method for purification of lentiviral vectors.
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Accordingly, it would have been obvious for an ordinary skilled artisan before the effective filing date of the present application to modify the teachings of Dizon-Maspat et al by also at least utilizing the disclosed SPTFF system comprising one or more membranes with a MWCO of about 30 kDa and about 300 kDa in a scalable manufacturing process to produce/purify/concentrate recombinant lentiviral vectors harvested from a serum-free suspension cell culture system, in light of the teachings of Arunkumar et al, Hong et al and Qu et al as presented above.
An ordinary skilled artisan would have been motivated to carry out the above modifications because: (i) Arunkumar et al already taught a method for concentrating a solution of a biological macromolecule that is retained on at least two semi-permeable membranes that have different molecular weight cutoffs (MWCOs) by passing the solution through a hybrid configuration of said semi-permeable membranes staged in series in a single pass tangential flow filtration (SPTFF) apparatus, wherein the final membrane in the series of membranes has a larger MWCO than the preceding membrane or membranes (e.g., the 30-30-50 kDa hybrid configuration for an antibody with MW of about 140-150 kDa), and wherein the biological macromolecule includes a nucleic acid, a DNA (e.g., chromosomal DNA, genomic DNA, cDNA, viral DNA, expression vector DNA, plasmid DNA, a viral vector DNA), an RNA and a virus; (ii) Hong et al already disclosed a method for large-scale preparation of a purified preparation of a recombinant lentiviral vector comprising ultrafiltration of a filtrate containing the recombinant lentiviral vector using an ultrafiltration membrane with a cut-off value of 300-500 K; followed by purifying a filtrate containing a recombinant lentiviral vector by means of chromatography that include anion chromatography and/or size exclusion chromatography; and (iii) Qu et al also disclosed at least a scalable manufacturing process to produce recombinant lentiviral vectors in serum-free suspension cell culture system (e.g., a spinner flask cell culture) to meet anticipated demand for human gene therapy, wherein the process includes at least steps using tangential flow filtration to reduce the volume and buffer exchange, and to obtain final lentiviral vector titer.
An ordinary skilled artisan would have a reasonable expectation of success in light of the teachings of Dizon-Maspat et al, Arunkumar et al, Hong et al and Qu et al as set forth above; coupled with a high level of skill of an ordinary skilled artisan in the relevant art.
The modified method resulting from the combined teachings of Dizon-Maspat et al, Arunkumar et al, Hong et al and Qu et al is indistinguishable and encompassed by the presently claimed invention.
Therefore, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Claim 70 is rejected under 35 U.S.C. 103 as being unpatentable over Dizon-Maspat et al (Biotechnology and Bioengineering 109:962-970, 2011) in view of Arunkumar et al (WO 2019/236811; IDS), Hong et al (US 12,018,293) and Qu et al (WO 2014/145578; IDS) as applied to claims 53-62, 64-69 and 71-72 above, and further in view of Noyes et al (WO 2020/191369).
The combined teachings of Dizon-Maspat et al, Arunkumar et al, Hong et al and Qu et al were presented above. However, none of the cited references teach specifically the use of a denarase DNA endonuclease.
Before the effective filing date of the present application (06/11/2020), Noyes et al already taught using a nuclease such as Benzonase or Denarase to treat a sample containing cell-derived extracellular vesicles (EVs) to digest nucleic acid associated with EVs prior to a cation exchange chromatography (CEX) resin and/or an anion exchange chromatography (AEX) resin process (Abstract; particularly paragraphs [0024], [0304]-[0305]).
Accordingly, it would have been obvious for an ordinary skilled artisan before the effective filing date of the present application to further modify the combined teachings of Dizon-Maspat et al, Arunkumar et al, Hong et al and Qu et al by also selecting Denarase as a DNA endonuclease to reduce or decrease the amount of a nucleic acid impurity in harvested or a preparation of recombinant lentiviral vectors, in light of the teachings of Noyes et al as presented above.
An ordinary skilled artisan would have been motivated to further carry out the above modification because Noyes et al already taught using a nuclease such as Benzonase or Denarase to treat a sample containing cell-derived extracellular vesicles (EVs) to digest nucleic acid associated with EVs prior to a cation exchange chromatography (CEX) resin and/or an anion exchange chromatography (AEX) resin process.
An ordinary skilled artisan would have a reasonable expectation of success in light of the teachings of Dizon-Maspat et al, Arunkumar et al, Hong et al, Qu et al and Noyes et al as set forth above; coupled with a high level of skill of an ordinary skilled artisan in the relevant art.
The modified method resulting from the combined teachings of Dizon-Maspat et al, Arunkumar et al, Hong et al, Qu et al and Noyes et al is indistinguishable and encompassed by the presently claimed invention.
Therefore, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Conclusions
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Quang Nguyen, Ph.D., at (571) 272-0776.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s acting SPE, James Douglas (Doug) Schultz, Ph.D., may be reached at (571) 272-0763.
To aid in correlating any papers for this application, all further correspondence regarding this application should be directed to Group Art Unit 1631; Central Fax No. (571) 273-8300.
Any inquiry of a general nature or relating to the status of this application or proceeding should be directed to (571) 272-0547.
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/QUANG NGUYEN/Primary Examiner, Art Unit 1631