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 .
Claims 1, 5, 6, 9, 20, 21, 25-33 and 35-39 are pending and examined on the merits.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 2/28/25 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
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, 5, 6, 9, 20, 21, 25-33 and 35-39 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.
Claim 1 recites, “in the AAV product have a deamidated N57 on VP1.” However, amino acid 57 on VP1 is indefinite since it is unclear where on VP1 this N57 is located. Is the VP1 full-length or a truncated mutant of VP1. It is suggested that a corresponding SEQ ID NO: representing the VP1 amino acid sequence also be present in the claim to clarify the position of N57. Claims 5, 6, 9, 20, 21, 25-33 and 35-39 are also rejected because they depend from claim 1, but do not remedy this deficiency.
Claim Rejections - 35 USC § 102
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.
Claim(s) 1, 5, 6, 9, 20, 21, 25, 26, 27, 28, 36 and 37 are rejected under 35 U.S.C. 102a1 as being anticipated by Jin et al. (US PGPub 2021/0041451).
The claimed invention is drawn to an adenovirus-associated virus (AAV) product comprising functional capsids containing a transgene, wherein less than 5% or 1% of the capsids in the AAV product have a deamidated N57 on VP1. The AAV product comprises less than 10% non-functional capsids. Deamidation is detected by liquid chromatography-mass spectrometry (LC/MS).
The claimed invention also requires a method of producing the AAV product from a composition comprising AAV capsids, the method comprising separating non-functional capsids in the composition from functional capsids containing a transgene by either:
hydrophobic interaction chromatography (HIC);
anion-exchange chromatography with a fatty acid mobile phase; or
a mixed-mode anion-exchange chromatography.
The separating further requires anion exchange chromatography (AEX) and HIC is performed before AEX, which does not require fatty acid mobile phase.
Wherein the AAV product has greater transgene expression in a host cell than a control AAV product purified by a method consisting of (i) ultracentrifugation or (ii) AEX without fatty acid mobile phase.
Wherein the AAV product has a lower ratio of VP1 to VP2 than a control AAV product purified by a method consisting of (i) ultracentrifugation or (ii) AEX without fatty acid mobile phase.
MPEP 2112 provides guidance pertaining to inherency. In the instant case, “discovery of new properties of a known material does not make claims reciting those properties novel”.
Jin et al. teach producing AAV capsids and using LC/MS to characterize the heterogeneity of the AAV capsids. For example, LC/MS can determine the presence of N-terminal acetylation of the AAV capsid proteins. [see paragraph 8] The AAV capsids are also taught to be used in the delivery of a therapeutic transgene. [see paragraphs 8, 12 and 37] While Jin et al. teach AAV capsids can be deamidated at various positions, including amino acid 57 of the full-length VP1 protein, they also teach that deamidation can be decreased and that the VP1 proteins are only subject to N-terminal acetylation. [see paragraphs 8, 29, 177 and 194] This would result in AAV capsid proteins lacking deamidation. Jin et al. further teach that AAV capsids can be processed and purified using chromatography techniques. More specifically, “AAV particles may be isolated or purified using one or more of the following purification steps: equilibrium centrifugation; flow-through anionic exchange filtration; tangential flow filtration (TFF) for concentrating the AAV particles; AAV capture by apatite chromatography; heat inactivation of helper virus; AAV capture by hydrophobic interaction chromatography; buffer exchange by size exclusion chromatography (SEC); nanofiltration; and AAV capture by anionic exchange chromatography, cationic exchange chromatography, or affinity chromatography. These steps may be used alone, in various combinations, or in different orders. In some embodiments, the method comprises all the steps in the order as described below….” [see paragraph 192] In view Jin et al. teaching a AAV capsid protein that possesses the same structure as presently claimed and the use of chromatography purification techniques, including HIC and AEX (that makes no mention of fatty acid mobile phase), which can be used in any order, and the AAV capsid contains a transgene, the AAV capsid of Jin et al. would also inherently possess the claimed greater transgene expression in a host cell compared to a control AAV product purified by ultracentrifugation or AEX (w/o fatty acid mobile phase) and the lower ratio of VP1 to VP2 than a control AAV product purified by ultracentrifugation or AEX (w/o fatty acid mobile phase).
Therefore, Jin et al. anticipate the instant invention.
Claim(s) 1, 5, 6, 9 and 35 are rejected under 35 U.S.C. 102a1 as being anticipated by Maga et al. (WO/22/094461).
The claimed invention is drawn to an adenovirus-associated virus (AAV) product comprising functional capsids containing a transgene, wherein less than 5% or 1% of the capsids in the AAV product have a deamidated N57 on VP1. The AAV product comprises less than 10% non-functional capsids.
The claimed invention also requires the administration of this AAV to a subject in need a protein produced by the transgene.
The deamidated VP1 is detected by liquid chromatography-mass spectrometry.
Maga et al. teach the removal of AAV compositions that may contain impurities, such as AAV capsids with deamidated amino acids. The capsid proteins with deamidated amino acids are impurities and are removed with chromatography techniques, such as anion exchange and ultracentrifugation. [see paragraph 27] This removal would result in no AAV capsids possessing deamidated N57 VP1 proteins and functional AAV capsids would remain. Maga et al. also teach “Thus, rAAV with deamidated capsids (or deamidated rAAV) are impurities that may be incapable of infecting cells or a cell infected with the deamidated rAAV may be unable to express (e.g. by transcription and/or by translation) an element (e.g. nucleotide sequence, protein, etc.) of interest. Deamidated rAAV may also contribute to decreased effectiveness per unit dose of capsid and may increase the risk of an immune response due to a needed increase of foreign proteins being introduced into the patient for an effective amount of heavy/full/partially full capsid. Accordingly, AEX and ZUC processing reduces the concentration of rAAV with deamidated capsids. The deamidation level of VPl protein at the N-terminus of GOI1, GOI2, and GOB are quantified by Liquid Chromatography-Mass Spectrometry (LC-MS).” [see paragraph 219] Maga et al. further teach “The AAV structural simplicity and nonpathogenic nature make recombinant AAV (rAAV) a useful gene therapy vector. AAV gene therapy vectors can infect both replicating and non-replicating cells and introduce transgenes without integrating into the genome of the host cell.” [see paragraph 2] and “The recombinant AA V can also be used to produce a protein of interest in vivo, for example in an animal such as a mammal. Some embodiments provide a method for producing a protein of interest in vivo, where the method includes providing a recombinant AAV
comprising a nucleotide sequence encoding the protein of interest; and administering the
recombinant AAV to the subject, whereby the recombinant AAV expresses the protein of
interest in the subject.” [see paragraph 125].
Therefore, Maga et al. anticipate the instant 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.
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.
Claim(s) 29-32 are rejected under 35 U.S.C. 103 as being unpatentable over Jin et al. as applied to claims 1, 5, 6, 9, 20, 21, 25, 26, 27, 28, 36 and 37 above, and further in view of Sanaie et al. (US PGPub 2018/0265543).
The claimed invention also requires the use of an AEX with a fatty acid mobile phase that comprises octanoic acid (also known as caprylate) or the use of a mixed mode resin chromatography, such as hydrophobic anion exchange resin.
The teahcings of Jin et al. are summarized above, while they teach using several different chromatography techniques, including AEX and HIC, they do not specifically teach the use of AEX with a fatty acid mobile phase that comprises octanoic acid (also known as caprylate) or the use of a mixed mode resin chromatography, such as hydrophobic anion exchange resin.
Sanaie et al. teach the purification of antibodies using chromatography. [see claims 1-20] Specifically, they teach “In additional aspects, the methods provided herein may further comprise washing the protein A chromatography matrix with at least one additional wash solution that comprises at least one additive, such as arginine, guanidine, sodium chloride, or caprylate.” [see paragraph 6] and “In some embodiments, the method further comprises loading the protein A purified antibody onto a mixed-mode chromatography matrix to obtain a mixed-mode purified antibody. In some embodiments, the method further comprises loading the cation exchange purified antibody onto a mixed-mode chromatography matrix to obtain a mixed-mode purified antibody. In some embodiments, the mixed-mode chromatography step comprises anion exchange and hydrophobic interaction mechanisms. In certain embodiments, the mixed-mode chromatography step comprises a matrix selected from the group consisting of a Capto Adhere matrix, a Capto Adhere ImpRes matrix, a Capto MMC matrix, and a Capto MMC ImpRes matrix.” [see paragraph 12]
It would have been obvious to one of ordinary skill in the art to modify the methods taught by Jin et al. in order to use a AEX with a octanoic acid mobile phase or a mixed-mode resin, such as a hydrophobic anion exchange resin. One would have been motivated to do so, given the suggestion by Jin et al. that AAV capsids can be purified by different forms of chromatography, including AEX and HIC. There would have been a reasonable expectation of success, given the knowledge that caprylate (octanoic acid) can be used with chromatography and that AEX and mixed mode chromatography (mixed-mode chromatography comprising anion exchange and hydrophobic interaction mechanism) can be used to purify proteins, such as antibodies, and that as taught by Sanaie et al. Thus the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Claim(s) 33 and 38-39 are rejected under 35 U.S.C. 103 as being unpatentable over Jin et al. as applied to claims 1, 5, 6, 9, 20, 21, 25, 26, 27, 28, 36 and 37 above, and further in view of Maga et al. (WO/22/094461).
The claimed invention also requires transfecting cells in a bioreactor to produce unseparated capsids, wherein the capsids are maintained in the bioreactor for up to two days after transfection, and the AAV capsids are harvested at 2 days post transfection and the temperature of the bioreactor after transfection is kept at 37-degrees Celsius.
The teachings of Jin et al. are summarized above, however, they do not teach specifically incubating transfected cells in a bioreactor to produce unseparated capsids, wherein the capsids are maintained in the bioreactor for up to two days after transfection, and the AAV capsids are harvested at 2 days post transfection and the temperature of the bioreactor after transfection is kept at 37-degrees Celsius.
Maga et al. with regard to produce AAV capsids, “In various embodiments, the cells after transfection are cultured for about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 72 hours, about 96 hours, about 120 hours, about 144 hours, about 168 hours, about 192 hours, about 216 hours, about 240 hours, or a time between any of these two time points after transfection.
As previously noted, the increased concentrations of therapeutically effective rAAV
particles are an economically viable quantity that can be processed each time by ZUC. In one
example, the process of various embodiments can allow for greater concentrations of rAAV to
be produced such that larger cell culture volumes can be used for rAAV production. For
example, host cells capable of producing rAAV can be cultured in a volume of at least 5
milliliters (mL), at least 10 mL, at least 20 mL, at least 50 mL, at least 100 mL, at least 500
mL, at least 1 liter (L), at least 10 L, at least 50 L, at least lO0L, at least 250 L, at least 500 L,
at least 1000 L, at least 1500 L, at least 2000 L, or at least 2500 L. Culturing can also occur in
a spin tube(s), a shake flask(s), or a bioreactor(s).
Clarification: To remove rAAV virions from cultured host cells, a number of
methods can be employed. In one example, the cells are lysed and the virus can be purified.
Alternatively, the virus is expressed into the supernatant…” [see paragraphs 148-150]
It would have been obvious to one of ordinary skill in the art to modify the methods taught by Jin et al. in order to incubated transfected cells in a bioreactor to produce unseparated capsids, wherein the capsids are maintained in the bioreactor for up to two days after transfection, and the AAV capsids are harvested at 2 days post transfection and the temperature of the bioreactor after transfection is kept at 37-degrees Celsius. One would have been motivated to do so, given the suggestion by Jin et al. that AAV capsids can be produced by transfecting host cells and culturing the host cells in a bioreactor (see paragraph 181). There would have been a reasonable expectation of success, given the knowledge that host cells transfected for expressing AAV capsids can be cultured for about 48 hours and then virus can be harvested, and that as taught by Maga et al. Furthermore, while Maga et al. do not specifically teach the temperature of 37 degrees Celsius for incubation, one of ordinary skill in the art would optimize the temperature for cell culture, thereby arriving at 37 degrees Celsius (MPEP § 2144.05 (II) (A) states, “…Optimization Within Prior Art Conditions or Through Routine Experimentation…“[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to dis-cover the optimum or workable ranges by routine experimentation…”). Thus the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BENJAMIN P BLUMEL whose telephone number is (571)272-4960. The examiner can normally be reached M-F 8-5 EST.
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/BENJAMIN P BLUMEL/Primary Examiner, Art Unit 1671
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