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 .
Applicant’s amendment submitted on 11/18/2025 is acknowledged. All of the amended claims filed 11/18/2025, claims 1-11 and 13-17, are under examination on the merits.
Objections Withdrawn
The previous objections are hereby withdrawn due to Applicant’s amendment submitted 11/18/2025:
Specification
Claims 2, 5-6, 11, 13-14, and 17 for minor informalities
Prior Rejections Withdrawn
The previous rejections are hereby withdrawn due to Applicant’s amendment submitted 11/18/2025:
35 U.S.C. §112(b): claims 6-7 and 14-15 as being indefinite
35 U.S.C. §102: claims 1-2, 5, 7-11, 13, 15, and 16.
35 U.S.C. §103: claims 3-4, 6, and 17.
Claim Interpretation
The term “milieu” is not defined in the specification. Merriam-Webster dictionary defines “milieu” to be: “the physical or social setting in which something occurs or develops.” In the instance case, the examiner is interpreting milieu to mean buffer.
New Objections
Claim Objections
Claim 14 is objected to because of the following informalities: claim 14 has an error on line 2, where it is missing “is” between “milieu” and “in the range of”. Appropriate correction is required.
New Rejections
Claim Rejections - 35 USC § 112
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.
Claims 13 and 14 are 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 13 depends from claim 5 but does not require further limitation of the claimed subject matter. Each claim requires the pH value of the second alkaline milieu is in the range of pH 8.0 to pH 9.0.
Claim 14 depends from claim 6 but does not require further limitation of the claimed subject matter. Each claim requires the pH value of the third alkaline milieu is in the range of pH 8.5 to pH 10.5.
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 § 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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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 1-11 and 13-17 are rejected under 35 U.S.C. 103 as being unpatentable over Fiedler et al. (WO 2019133677 A1, published 7/4/2019; hereinafter referred to as “Fiedler”).
The claimed invention encompasses a method for the separation or depletion of empty AAV capsids from full AAV capsids in an aqueous mixture comprising empty and full AAV capsids, the method comprising: contacting the mixture with a primary amino groups bearing solid phase surface in a first alkaline milieu whereby (i) full AAV capsids bind to the solid phase surface whereas empty AAV capsids at least partially do not bind to the solid phase surface, and optionally contacting the solid phase with a second alkaline milieu of a pH value higher than the pH value of the first alkaline milieu, wherein bound empty AAV capsids are at least partially eluted, with the proviso that the second alkaline milieu does not elute full AAV capsids from the solid phase surface; or (ii) both full and empty AAV capsids bind to the solid phase surface, and subsequently contacting the solid phase with a second alkaline milieu of a pH value higher than the pH value of the first alkaline milieu, wherein empty AAV capsids are at least partially eluted, with the proviso that the second alkaline milieu does not elute full AAV capsids from the solid phase surface, as recited in claim 1. In another embodiment, the pH value of the first alkaline milieu is in the range of greater than pH 7 to pH 8, as recited in claim 2. In another embodiment of the claimed invention, after the empty AAV capsids are at least partially eluted with the second milieu, contacting the solid phase surface with a third alkaline milieu having a pH value greater than the pH value of the second milieu, as recited in claim 3.
In another embodiment of the claimed invention, after contacting the solid phase surface with the third alkaline milieu, contacting the solid phase surface with a fourth alkaline milieu having a pH value less than the pH value of the third or second alkaline milieu but a higher salt concentration compared to the first, second, or third alkaline milieu, as recited in claim 4.
In a specific embodiment, the pH value of the second alkaline milieu is in the range of pH 8.0 to pH 9.0, as recited in claims 5 and 13. In other embodiments, the pH value of the third alkaline milieu is in the range of pH 8.5 to pH 10.5, as recited in claims 6 and 14. In a particular embodiment, the alkaline milieus comprise magnesium ions at a concentration in the range of 1.0 mM to 5.0 mM, as recited in claim 8, or more specifically at a concentration of 1.5 mM to 3.0 mM, as recited in claim 16. In another embodiment, the full and empty AAV capsids are of any serotype, as recited in claim 9. In a more specific embodiment, the full and empty AAV capsids are selected from the group consisting of natural and recombinant serotypes, chimeric, mixed, and combinations thereof, as recited in claim 17. In one embodiment, the primary amino groups bearing solid phase surface is arranged in a chromatography device, as recited in claim 10. In a particular embodiment, the primary amino groups bearing solid phase surface is selected from the group consisting of a monolith, a column of packed particles, a column of packed nanofibers, a membrane adsorber, and a hydrogel, as recited in claim 11.
Alternatively, the first, second, third, and/or fourth alkaline milieu comprises a salt concentration corresponding to the concentration of up to 1M of an alkali metal salt, as recited in claim 7, or more specifically wherein the first, second, third and/or fourth alkaline milieu comprises a salt concentration corresponding to the concentration of 1 mM to 1,000 mM, as recited in claim 15.
The Prior Art
Fiedler teaches methods of producing and purifying full adeno-associated virus (AAV) capsids from a concentrated AAV fraction comprising empty AAV capsids and full AAV capsids (Abstract; para. [0069]). Fiedler’s methods encompass embodiments wherein the solution containing the AAV particles undergoes ion exchange chromatography, such as anion exchange that can remove residual particle contaminants, acidic impurities, proteases, and/or host cell DNA, and may be conducted with membrane-based separation (para. [00162]). The anion exchange support can be PEI-based resins (para. [00162]), which are described in the instant specification as bearing primary amines (spec, p. 9). Fiedler also teaches use of membrane adsorbers for loading viral particles (para. [0254]). Embodiments of Fiedler’s methods include a first alkaline milieu of pH 7.4 – pH 7.8 and elution with an additional alkaline milieu with pH 8.0 (paras. [0195], [0197-198]), which meet the claim limitations of the first and second buffers (milieus). Additionally, the elution buffer contained a higher concentration of NaCl (750 mM) than the previous buffers (125 or 150 mM; paras [0196-0198]). See also examples 2-4 & 7, and Table 15. The elution buffer may comprise about 2 mM magnesium chloride (claims 8 & 53). Fiedler teaches that the AAV purified by its methods may be of the AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10 serotype, AAV11, AAV12, AAV13, serotypes, or an AAV modified by genetic engineering or that is chemically modified (para. [0076]).
Fiedler further discloses embodiments where three wash steps occur after loading an AAV containing solution onto an affinity resin targeted against AAV, wherein the first wash buffer has a pH from about 5.2 to about 6.8, the second buffer has a pH from about 7.5 to about 9.2, and the third buffer has a pH from about 7.3 to about 8.8 (Fiedler, claims 1, 15-16, & 20). Accordingly, the ranges of wash buffer pH taught by Fiedler allow for increasing pH from wash buffer 1 to wash buffer 2, and wash buffer 2 to wash buffer 3.
However, Fiedler does not specifically teach embodiments where a third alkaline milieu having a pH value greater than the pH value of the second milieu is contacted with the solid phase surface.
It would have been obvious to one of ordinary skill in the art to modify the methods specifically taught by Fiedler to render obvious the claimed methods. Fiedler teaches ranges of wash buffer pH encompasses increasing pH from wash buffer 1 to wash buffer 2, and from wash buffer 2 to wash buffer 3. It would have been obvious to one of ordinary skill in the art that, based on Fiedler’s teachings of using wash buffer with higher pHs, such as 7.4-7.8, 8, or 8.5, because Fiedler also teaches wash buffers that have pHs of 7.4-7.8, 8, or 8.5. The claimed invention would have been obvious to one of ordinary skill in the art through routine optimization to find the pH buffers which would yield the best separation of empty capsids from full capsids. See MPEP §2144.05(I) and (II). One of ordinary skill in the art would have been motivated to purify full AAV capsids from empty capsids and other contaminants. Therefore, claims 1-11 and 13-17 were prima facie obvious before the priority date of the instant invention.
Conclusion
No claim is allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to JEFFREY MARK SIFFORD whose telephone number is (571)272-7289. The examiner can normally be reached 8:30 a.m. - 5:30 p.m. ET with alternating Fridays off.
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/JEFFREY MARK SIFFORD/Examiner, Art Unit 1671
/BENJAMIN P BLUMEL/Primary Examiner, Art Unit 1671
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