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
This application is a national stage entry of 35 U.S.C. 371 of PCT/EP2023/054954 (filed on 02/28/2023), which claims benefit to foreign EUROPEAN PATENT OFFICE (EPO) 22159915.2 (filed on 03/03/2022).
Claims Status
Claims 1-6 and 8-10 are pending and have been examined on the merits.
Claim Interpretation
For clarity of record the following comments are made regarding claim interpretation under broadest reasonable interpretation:
Claim 1 is drawn to a method of manufacturing an RNA- or DNA-containing virus particle in cell culture, such that the virus particle is obtained from culture medium or cell of the method. The claim does not specify how to viral particle is made, however, it is understood that some mechanism must exist for the RNA and DNA containing particle to be produced, as the method requires obtaining the virus particle from the culture media or cell. Therefore the result of the method can include viral like particles (VLP), like viral particles.
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.
Claims 1,3-6, and 10 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Barrett et al (US 2011/0262965 A1).
Barrett et al discloses method of manufacturing cell culture media with dipeptides that improved stability and conditions for cell culture (See, Abstract).
Regarding claim 1, Barrett et al disclosed that the invention can be used for virus production from mammalian cells comprising (a) contacting cell with a virus; and (b) cultivating the cell in a dipeptide containing cell culture media described therein that is suitable to promote virus production by the cell (See, ¶0139). This reads on the method comprising: providing a cell capable of producing said virus particle; contacting said cell with a culture medium comprising one or more dipeptides. Barrett et al discloses that to eliminate the potential for toxins in the cell culture, dipeptides such as alanyl-glutamine or glycyl-glutamine are used in place of glutamine in cell culture (See, ¶0005). This reads on, wherein one dipeptide is glycyl-glutamine.
Barrett et al also disclosed that the method can be used to produce mammalian viruses, viral particles, and viral vectors; such as adeno-associated viruses (AAV), retroviruses, or lentiviruses (See, ¶0140). Further, the culture media from the cells of the method that have been infected, comprises viruses, such as recombinant virus, viral vectors, viral particles, and or components thereof (proteins or DNA or RNA). Barrett et al also disclosed that the viruses, viral vectors, viral particles or components can be isolated from the culture medium (See, ¶0140). This reads on, obtaining said RNA or DNA containing virus particle from said culture medium.
Regarding claim 3, following the discussion above, Barrett et al disclosed the virus particle can be AAV, retrovirus or lentivirus (See, ¶0140). This reads on, wherein the virus particle is at least one… AAV or lentivirus.
Regarding claim 4, following discussion above, Barret et al disclosed that the concentration of the dipeptides can range from about 0.5 g/L to about 20 g/L or about 5 g/L to about 10 g/L, which equals 2.46 mM to 98.4mM and 24.6 mM to 49.2 mM respectively (See, ¶0029). This reads on, wherein the dipeptide is present in the culture medium at a concentration of from 0.1mM to 20mM.
Regarding claim 5, following the discussion above, Barrett et al disclosed the cell culture medium has one or more dipeptides and can comprise: a carbohydrate, a vitamin, a salt, an inorganic element, a buffer agent, and an amino acid (See, ¶0017-19). This reads on the limitations of claim 5.
Regarding claims 6 and 10, following the discussion above, Barrett et al further disclosed that the cell culture medium is suitable to culturing mammalian cells, such as CHO cells, COS cells, VERO cells and HEK293 cells (See, ¶0020). This reads on, wherein the cell is… CHO cells, COS cells, VERO cell, and HEK293 cells of claim 6. This reads on, wherein the cell are HEK cells of claim 10.
Therefore claims 1,3-6, and 10 are anticipated by Barrett et al.
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.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Barrett et al (US 2011/0262965 A1).
The teachings of Barrett et al set forth above.
Regarding claim 9, following the discussion above, Barret et al disclosed that the concentration of the dipeptides can range from about 0.5 g/L to about 20 g/L or about 5 g/L to about 10 g/L, which equals 2.46 mM to 98.4mM and 24.6 mM to 49.2 mM respectively (See, ¶0029).
However, the concentration of the dipeptide would have been routinely optimized by one having ordinary skill in the art based on the culture conditions. Barrett et al teaches the concentration of the dipeptide at 2.46 mM to 98.4mM is effective to achieve culturing conditions for producing RNA- or DNA-containing viral particle. That means the conditions necessarily to achieve the RNA- or DNA-containing viral particle were result effective variables. Result effective variables would be optimized by routine experimentation by one having ordinary skill in the art. Furthermore, differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. See MPEP 2144.05(II)(A).
Therefore claim 9 is rendered obvious by Barrett et al.
Claims 1-6 and 8-10 are rejected under 35 U.S.C. 103 as being unpatentable over Piras et al (Molecular therapy-Methods & Clinical Development, 2016) and in view of Barrett et al (US 2011/0262965 A1); evidenced by Thermo Fisher™ formulation sheets (GlutaMAX™ and DMEM).
The teachings of Barrett et al are set forth above.
Piras et al teach the comparison of AAV8 packaged with Factor VIII (FVIII) in cell culture media and lysates (See, Abstract).
Regarding claims 1 and 8, Piras et al teaches the transfection of HEK293T/17 cells to produce AAV8 packaged with single stranded genome expressing human FVIII gene. The cell culture and the cells were harvested at days 3,5,6, and 7, then analyzed by ELISA for AAV8 capsid (See, p2 col 1 – col 2 paragraph 1, Figure 1). This reads on, method of manufacturing an RNA- or DNA- containing virus particle in cell culture, the method comprising: providing a cell capable of producing said virus particle;…obtaining said RNA or DNA containing virus particle from said culture medium or from said cell.
The methods of Piras et al teaches the culture media for cell culture and transfection consist of DMEM with 10% FBS with 2mmol/L of GlutaMAX™ (which contains L-alanyl-L-glutamine dipeptide; evidenced by Thermo Fisher™ website) (See, p4 col 1 paragraph 4). This reads on, contacting said cell with a culture medium comprising one or more dipeptides.
Piras et al does not teach that the dipeptide in the culture medium is glycyl-glutamine.
Barrett et al discloses that glutamine is routinely used in cell culture media but it is unstable and causes the creation of pyroglutamate and ammonia, which is toxic for cells (See, ¶0004). Barrett et al discloses that to eliminate the potential for toxins in the cell culture, dipeptides such as alanyl-glutamine or glycyl-glutamine are used in place of glutamine in cell culture (See, ¶0005).
Given that Piras et al and Barrett et al both teach methods of producing RNA- or DNA- containing virus particle in cell culture, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to substitute the alanyl-glutamine (GlutaMAX™) with glycyl-glutamine in the method taught by Piras et al in the method of producing nucleic acid containing virus particle in cell culture, as taught by Barrett et al for a similar purpose.
Both Piras et al and Barrett et al teach methods of producing nucleic acid containing virus particle in cell culture. The use of glycyl-glutamine in the place of alanyl-glutamine (GlutaMAX™) in Piras et al, is predictable use of prior art elements according to their established functions, leading to predictable result of improving cell culture conditions. This rationale aligns with the principle of KSR for a simple substitution of one known element for another to obtain predictable results (See, MPEP 2143).
Regarding claim 2, following the discussion above, Piras et al teaches the transfection of HEK293T/17 cells to produced AAV-FIII or AAV packaged with human Factor IX (FIX) or AAV packaged with human protective protein/cathepsin A (PPCA). Cells and culture medium were harvested on day 3 and 6, analyzed by ELISA to quantify the AAV8 particles produced. Figure 2 shows that the media contains a large number AAV8 particles compared to the cells for all vectors (See, p2 col 2 paragraph 2 , Figure 2).
Piras et al teaches the quantification of the viral genome in cell lysates and culture media for HEK293T/17 cells transfected to produce AAV-FVIII. Cells and medium were harvested 6 days after transfection. qPCR determined that media contained (avg) 85.9% of FVIII viral genomes and the ration of full to empty AAV particles is equivalent in media and cell lysates (See, p3 col1 paragraph 1, Figure 3). Piras et al teaches that qPCR shows 86% viral genomes in media compared to 90% capsids (See, p3 col 2). This reads on, wherein a full/empty ratio is determined by division of genome titer by PCR and capsid titer by ELISA.
Regarding claims 3 and 8, following the discussion above, Piras et al teaches the viral genomes are flanked by AAV2 inverted repeats and packaged in AAV8 capsids (See, p4 col 1 paragraph 4). This reads on, wherein the virus particle is at least one selected from the group consisting of…AAV of claim 3. This reads on, wherein the virus particle is selected from the group of AAV viruses AAV8 and AAV2 of claim 8.
Regarding claim 4, following the discussion above, Piras et al teaches the culture media for cell culture and transfection consist of DMEM with 10% FBS with 2mmol/L = 2mM of GlutaMAX™ (which contains L-alanyl-L-glutamine dipeptide) (See, p4 col 1 paragraph 4). This reads on, wherein the dipeptide is present in the culture medium at a concentration of from 0.1 mM to 20 mM of claim 4.
Regarding claim 5, following the discussion above, the method of Piras et al the culturing media consist of DMEM which contains glucose (carbohydrate), L-glutamine (free amino acid), potassium chloride (inorganic salt), sodium bicarbonate (buffer agent), and riboflavin (vitamin), evidenced by the Thermo Fisher™ formulation sheet. This reads on, wherein the culture medium further comprises: at least one carbohydrate, at least one free amino acid, at least one inorganic salt, a buffering agent, and/ or at least one vitamin of claim 5.
Regarding claims 6 and 10, following the discussion above, Piras et al teaches the transfection of HEK293T/17 cells to produce AAV packaged genome. This reads on, wherein the cell is… HEK cells of claims 6 and 10.
Regarding claim 9, following the discussion above, Piras et al does not teach a concentration between 5mM and 10mM.
However, the concentration of the dipeptide would have been routinely optimized by one having ordinary skill in the art based on the other culture conditions. Piras et al teaches the concentration of the dipeptide at 2 mM is effective to achieve culturing conditions for producing RNA- or DNA-containing viral particle. That means the conditions necessarily to achieve the RNA- or DNA-containing viral particle were result effective variables. Result effective variables would be optimized by routine experimentation by one having ordinary skill in the art. Furthermore, differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. See MPEP 2144.05(II)(A).
Therefore, claims 1-6 and 8-10 are rendered obvious over Prias et al in view of Barrett et al.
Conclusion
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/CAROLINE M LARA/Examiner, Art Unit 1633
/ALLISON M FOX/Primary Examiner, Art Unit 1633
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