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 .
Claim Status
Applicant’s amendment submitted 6/25/2026 is acknowledged. All of the amended claims filed 6/25/2026, claims 1-11 and 13-17, are under examination on the merits.
Objections and Rejections Withdrawn
The previous objections and rejections are hereby withdrawn due to Applicant’s amendment submitted 6/25/2026:
Claim objections: claim 14 for informalities.
35 U.S.C. §112(d): claims 13 and 14.
Maintained Rejections
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
(Previous Rejection Maintained) 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).
Applicant’s arguments have been carefully considered but are found unpersuasive
Applicant presents the following arguments:
The cited reference does not render Applicant’s claimed invention prima facie obvious.
The presently claimed invention is directed to a method for separating full AAV capsids from empty AAV capsids from an aqueous mixture. The method comprises contacting the mixture with a solid phase surface bearing primary amino groups in a first alkaline milieu. Fiedler simply does not teach or suggest the method of claim 1 since this step is not taught. Thus, Fiedler does not render the invention prima facie obvious.
Fiedler discloses methods of producing and purifying adeno-associated virus. As summarized in the Abstract, "AAV is loaded onto an affinity resin, wash steps are undertaken, and AAV is eluted from the affinity resin. Various buffers are disclosed for use in the wash steps and elution." The method of Fiedler can include an optional pre-purification step using anion exchange (AEX) chromatography. Fiedler lists various contaminants that can be removed by this AEX step, such as proteases and host cell DNA. (See, for example, paragraphs [00127] and [00162].) Applicant emphasizes that Fiedler in no way teaches that the AEX step provides for the separation or depletion of empty AAV capsids from full AAV capsids. Furthermore and significantly, if the pre-purification AEX step is used, Fiedler encourages and exemplifies that the anion exchange chromatography is performed under conditions that allow the AAV to flow through the AEX column ("the desired AAV does not bind to the chromatography resin" also referred to as "non-binding mode"). See, for example, paragraph [00184] and Examples 4-7 of Fiedler. This teaching is clearly contrary to the method of instant claim 1 in which full AAV capsids bind to the solid phase surface in embodiment 1 and both full and empty AAV capsids bind to the solid phase surface in embodiment 2.
The examiner further referred to paragraph [0195] of Fiedler which is the first paragraph of Example 2. Example 2 is directed to production of AAV8, a particular AAV subtype. Paragraph [0195] describes a pre-purification step in which the viral particles were loaded onto a membrane adsorber having a Mustang Q surface, i.e., a surface with quaternary ammonium groups, not with a primary amino groups bearing solid surface, as specified in instant claim 1. Fiedler specifically discloses that the loading was performed at "nonbinding conditions" for the AAV. Note that Applicant uses columns with quaternary amine groups as a negative control.
The optional AEX step disclosed by Fiedler does not teach or suggest using a primary amino groups bearing solid phase surface whereby (i) full AAV capsids bind to the solid phase surface or (ii) both full and empty AAV capsids bind to the solid phase surface.
The examiner further referred to paragraphs [0197] and [0198] of Fiedler, which are paragraphs 2 and 3 of Example 2. As noted above, Example 2 is directed to production of AAV8 and paragraphs [0197] and [0198] of Example 2 exemplify the affinity chromatography step using an affinity matrix specifically designed for selectively binding the AAV8 subtype, specifically POROSᵀ CaptureSelectᵀ AAV8 Affinity Matrix. One of ordinary skill in the art would read Fiedler as teaching that affinity resins are designed to bind certain AAV subtypes based on the chosen affinity ligand and allow strip away of impurities, but they do not discriminate between capsids carrying the genetic payload and those that are empty. Fiedler in no way teaches or suggests that the affinity chromatography step provides for the separation or depletion of empty AAV capsids from full AAV capsids.
The affinity chromatography step disclosed by Fiedler does not teach or suggest using a primary amino groups bearing solid phase surface whereby (i) full AAV capsids bind to the solid phase surface or (ii) both full and empty AAV capsids bind to the solid phase surface.
The Examiner cited Fiedler at paragraph [0069] as "teaching methods of producing and purifying full adeno-associated virus (AAV) capsids from a concentrated AAV fraction comprising empty AAV capsids and full AAV capsids." However, Applicant cannot find any description in Fiedler of how to accomplish this.
The Examiner asserted that it would have been obvious to one of ordinary skill in the art
to modify the methods specifically taught by Fiedler to arrive at the claimed method. In particular, the Examiner asserted that it 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. Applicant respectfully disagrees. While various washes and pH ranges are disclosed by Fiedler, they are not disclosed in combination with anion exchange chromatography with a primary amino groups bearing solid phase as specified in instant claim 1. In particular, Fiedler does not suggest what methods and/or variables would be considered results effective to achieve this particular separation. Respectfully, any teaching or suggestion or reasonable expectation of success to modify Fiedler to arrive at the presently claimed invention is clearly missing and the rejection is based on reversible error. The rejection seems to be based on improper hindsight.
Significantly, prima facie obviousness is not established if all the elements of the rejected claim are not disclosed or suggested in the cited art. In re Ochiai, 71 F.3d 1565, 1569, 1570 (Fed. Cir. 1995). Also, the prior art reference (or references when combined) must teach or suggest the particular combination or modification. The teaching or suggestion to make the claimed combination and reasonable expectation of success must both be found in the prior art, and not based on applicant's disclosure. In re Vaeck, 947 F.2d 488, 20 USPQ2d 1438 (Fed. Cir. 1991). "It is impermissible, however, to simply engage in a hindsight reconstruction of the claimed invention, using applicant's structure as a template and selecting elements from references to fill the gaps." In re Gorman, 933 F.2d1 982, 987 (Fed. Cir. 1991) (emphasis added).
Obviousness also requires a reasonable expectation of success. "Where there is a reason to modify or combine the prior art to achieve the claimed invention, the claims may be rejected as prima facie obvious provided there is also a reasonable expectation of success. The reasonable expectation of success requirement refers to "the likelihood of success" in combining or modifying prior art disclosures to meet the limitations of the claimed invention. See Elekta Ltd. V. ZAP Surgical Sys., Inc., 81 F.4th 1368, 1375, 2023 USPQ2d 1100 (Fed. Cir. 2023) and Intelligent Bio-Sys., Inc. V. Illumina Cambridge Ltd., 821 F.3d 1359, 1367, 119 USPQ2d 1171, 1176 (Fed. Cir. 2016)." (MPEP 2143.02.I, emphasis added.)
In summary, the method of claim 1 is a novel method that is based on the surprising finding that a separation of full AAV capsids from empty AAV capsids can be achieved by means of a solid phase modified with primary amino groups. Fiedler in no way provides a likelihood of success meeting the limitations of the method of claim 1. The method of claim 1 would not have been obvious to one of ordinary skill in the art from a reading of Fiedler.
Thus, since Fiedler fails to teach or suggest all of the features of independent claim 1, a prima facie case of obviousness has not been established.
Applicant’s arguments are unpersuasive because:
Applicant is mischaracterizing Fiedler, because the supposed deficiencies described by Applicant are in fact taught by Fiedler. Fiedler teaches anion exchange support that can be PEI-based resins, which are described in the instant specification as bearing primary amines. Fiedler also teaches alkaline wash steps. The examiner also notes that the claimed method uses “comprising” language, and thus encompasses additional method steps and features. Further, “mere recognition of those latent properties does not render the otherwise obvious [method] unobvious and thereby patentable.” In re Prindle, 297 F.2d 251, 254 (CCPA 1962). Mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention. In re Wiseman, 596 F.2d 1019, 201 USPQ 658 (CCPA 1979). In response to applicant’s argument that Fiedler’s methods, which encompass the active steps claimed herein, fail to mention teach that the AEX step provides for the separation or depletion of empty AAV capsids from full AAV capsids, the fact that applicant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). However, even beyond that, and as pointed out in the previous action, Fiedler explicitly describes its methods pertaining to separating full capsids from a solution of full and empty capsids (para. [0069]).
Applicant is reminded that preferred embodiments are not the only teaching of a reference.
“The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain.” In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983) (quoting In re Lemelson, 397 F.2d 1006, 1009, 158 USPQ 275, 277 (CCPA 1968)).
A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Laboratories, 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989). See also > Upsher-Smith Labs. v. Pamlab, LLC, 412 F.3d 1319, 1323, 75 USPQ2d 1213, 1215 (Fed. Cir. 2005)(reference disclosing optional inclusion of a particular component teaches compositions that both do and do not contain that component); Celeritas Technologies Ltd. v. Rockwell International Corp., 150 F.3d 1354, 1361, 47 USPQ2d 1516, 1522-23 (Fed. Cir. 1998) (The court held that the prior art anticipated the claims even though it taught away from the claimed invention. “The fact that a modem with a single carrier data signal is shown to be less than optimal does not vitiate the fact that it is disclosed.”).
Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). “A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use.” In re Gurley, 27 F.3d 551, 554, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994). Furthermore, “[t]he prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed….” In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004).
Regarding Example 2 describing a pre-purification step, the claimed method uses comprising language, so having an additional step does not teach away from the obvious method.
Regarding the optional AEX step disclosed by Fiedler not teaching or suggesting using a primary amino groups bearing solid phase surface whereby (i) full AAV capsids bind to the solid phase surface or (ii) both full and empty AAV capsids bind to the solid phase surface, that is a latent property of AEX, see description of latent properties above, and Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). “When the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not.” In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). “Products of identical chemical composition can not have mutually exclusive properties.” A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990).
Regarding Fiedler in no way teaches or suggests that the affinity chromatography step provides for the separation or depletion of empty AAV capsids from full AAV capsids, Fiedler does (para. 69) teach methods of purifying full AAV capsids from a concentrated AAV fraction comprising empty AAV capsids and full AAV capsids. Just because they are doing it for a different reason than Applicant does not mean it is not obvious. Even if Fiedler had a completely different goal, which they don't, their obvious steps match the instant claims’. Provided herein, and as previously discussed at the locations of the reference cited by the examiner, these methods can be found.
Regarding various washes and pH ranges not being obvious to optimize, the various washes and pH ranges do not have to be precisely disclosed, as this is a rejection under 35 U.S.C. §103, rather than 35 U.S.C. §102. One of ordinary skill in the art understands that one must utilize buffers with certain pHs for the resins to work. For example, if provided a very low pH, the protons are going to interfere with binding.
The previously discussed paragraphs 197 and 198 of Fiedler demonstrate that pH is an important variable, because they change it there, even if not related to AEX. A person of ordinary skill in the art knows that you must utilize certain pHs with anion exchange, cation exchange, and even there, with affinity resins, like in paragraph 197. Applicant disagrees that one of ordinary skill in the art would be able to optimize the conditions of such a buffer, but paragraphs 197-198 make it clear that pHs of buffers are important for columns, and the general knowledge in the art is that AEX equally uses washing and elution buffers of particular pHs. This is because primary amines have an isoelectric point that is important to consider. One of ordinary skill in the art is aware that there will be different pHs because one can completely shut down the column if there are, for example, too many anions in the buffer. There is no requirement that an “express, written motivation to combine must appear in prior art references before a finding of obviousness.” See Ruiz v. A.B. Chance Co., 357 F.3d 1270, 1276, 69 USPQ2d 1686, 1690 (Fed. Cir. 2004).
Regarding a reasonable expectation of success, Applicant is merely asserting that there’s no reasonable expectation of success but not elaborating on why someone reading Fiedler, including the methods it discloses, which there are many, would lack a reasonable expectation of success in carrying out the instant method. Applicant is either opining or applying an incorrect legal standard. The examiner agrees that each and every element must be taught, but in the instant case, all of the elements are contemplated in the rejection. An expressly written motivation is not required. In response to applicant’s argument that the examiner’s conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant’s disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Regarding Applicant’s alleged surprising result, the examiner notes that full AAV capsids are naturally heavier than empty AAV capsids, so it is obvious that they could be separated by that fact alone, even in the absence of any other considerations. Even utilizing primary amine groups, that is not surprising when that is a method that Fiedler teaches and renders obvious. Applicant indicates that the methods claimed allow separation of full and empty capsids, and provide AEX as a component of the method, but the prior art already knew that a method comprising AEX could be used to separate full and empty capsids. Additionally, the method of claim 1 has an open transitional phrase, and so there’s nothing surprising about being able to separate full AAV capsids from empty AAV capsids with a method comprising an AEX step, when one could include additional steps. Additionally, Applicant has not justified why that their result is particularly surprising. They did not show any surprising finding, because the method is open, so every single type of method can be used, and the fact is that there is a weight difference in full vs empty capsids, so it is not surprising that a method comprising AEX separates empty vs full AAV capsids.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Michael Allen can be reached at 571-270-3497. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JEFFREY MARK SIFFORD/Examiner, Art Unit 1671 /Michael Allen/Supervisory Patent Examiner, Art Unit 1671
