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 1/26/2026 is acknowledged. Claims 8 and 15 are canceled, and new claims 19-22 are added.
Claims 1-7, 9-14, and 16-22 are under examination on the merits.
Withdrawn Objections
The previous objections are hereby withdrawn due to Applicant’s amendment submitted on 1/26/2026:
Claim objections: claim 18.
Withdrawn Rejections
The previous rejections are hereby withdrawn due to Applicant’s amendment submitted on 1/26/2026:
35 U.S.C. §112(b): claims 3-4 and 11-12 under 35 U.S.C. §112(b) as being indefinite.
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.
The following rejections under 35 U.S.C. §103 are still deemed proper and are maintained:
(Rejection Maintained) Claims 1-5, 7, and 19-22 are rejected under 35 U.S.C. 103 as being unpatentable over Mundle et al. (WO2013106337A1, published 7/18/2013; hereinafter referred to as “Mundle”) in further view of Wiggan et al. (Vaccine. 2011 Oct 6;29(43):7456-62. doi: 10.1016/j.vaccine.2011.07.054. Epub 2011 Jul 29. PMID: 21803103; hereinafter referred to as “Wiggan”) as evidenced by Sigma-Aldrich (retrieved from https://www.sigmaaldrich.com/US/en/product/sigma/p2443?srsltid=AfmBOor8aZHw8Os0SYlK4_ UQt_YXJHw1Xacws80-76h-HW_ZQFTvz9tG on 9/18/2015, published 2025, 5-page printout). This rejection is extended to the new Claims 19-22, which require the sugar to be trehalose (claims 19-20) or wherein the method does not include any step of endonuclease treatment (claims 21-22). Mundle’s methods encompass embodiments that do not require use of endonuclease treatment. For example, Mundle discloses a method comprising the steps of: a) recovering from a host cell culture flavivirus viral particles; b) applying the solution obtained from step (a) to an anion exchange chromatography resin; c) eluting the flavivirus viral particles from the anion exchange chromatography resin; d) subjecting the eluent from step (c) to TFF; and e) recovering the purified flavivirus viral particles (p. 7, lines 13-21; Mundle claim 1). Thus, Mundle’s methods do not require an endonuclease step, and the host cell DNA would inherently be removed by the anion exchange chromatography step disclosed by Mundle.
The rejection of claim 8 is withdrawn due to its cancelation in the amendment submitted 1/26/2026.
(Rejection Maintained) Claims 6, 9-14, and 16-18 are rejected under 35 U.S.C. 103 as being unpatentable over Mundle and Wiggan as evidenced by Sigma-Aldrich, as applied to claims Claims 1-5, 7, and 19-22 above, and further in view of Henderickx et al. (WO2012160199A1, published 11/29/2012; hereinafter referred to as “Henderickx”). The rejection of claim 15 is withdrawn due to its cancelation in the amendment submitted 1/26/2026.
Response to Arguments
Applicant's arguments filed 1/26/2026 have been fully considered but they are not persuasive.
Applicant presents the following arguments:
Mundle exclusively teaches that residual host cell DNA may be degraded by endonuclease treatment prior to chromatography and is entirely silent on any alternative strategy for host cell DNA removal, in contrast, present claim 1 addresses the technical problem of removing host cell DNA and further purification by a single chromatography step, thereby simplifying the process and improving robustness by eliminating enzyme dependency and the need for enzyme removal.
Mundle is directed to purification methods for flavivirus particles. However, the examples in Mundle exclusively investigate REPLIVAX attenuated flavivirus vector constructs which are based on West Nile virus. While West Nile virus and Dengue virus are both flaviviruses, it could not be readily expected that purification strategies developed for West Nile virus-based constructs would produce the same results for Dengue virus-based constructs.
Wiggan evaluates excipients such as trehalose, albumin, and Pluronic F-127 (poloxamer 407) solely for stabilizing flavivirus vaccines during storage, freeze-thaw cycles, and distributions, and is entirely silent on upstream production or purification processes. The Examiner asserts that it would have been obvious to incorporate the excipient composition disclosed in Wiggan into the purification process of Mundle; however, there is no teaching or suggestion in Wiggan that such excipients could be compatible with or beneficial for chromatographic purification. On the contrary, Wiggan teaches their use only for stabilizing the final vaccine formulation and does not mention purification at all. Thus, the two references Mundle and Wiggan solve unrelated technical problems, and a person skilled in the art would not have considered Wiggan when seeking to improve the purification methods described in Mundle. Moreover, even if the person of ordinary skill in the art had attempted to incorporate Wiggan’s excipients into the method of Mundle, there would have been no reasonable expectation that such modification would achieve effective host cell DNA removal while maintaining high viral titers.
As shown in Table 2 of the present application, mixing of a composition comprising a sugar, a protein, and a surfactant with the clarified harvest and subjecting the mixture to anion exchange chromatography leads to the efficient removal of host cell DNA below the detection level of the assay used. Further, when the clarified harvest was subjected to anion exchange chromatography, a strong loss of virus titer, whereas only a minimal loss of virus titer was observed when the clarified harvest was mixed with a composition comprising a sugar, a protein, and a surfactant. This effect is surprising, since excipients such as trehalose, albumin, and poloxamer 407 were described by Wiggan as stabilizing viral formulations, but not for enhancing purification performance.
A new claim, dependent on claim 9, has been introduced, requiring that “the method does not include any step of endonuclease treatment”.
Applicant’s arguments are found unpersuasive because:
It is true that Mundle discloses use of endonuclease to degrade DNA during viral purification. However, its methods encompass embodiments that do not require use of endonuclease treatment. For example, Mundle discloses a method comprising the steps of: a) recovering from a host cell culture flavivirus viral particles; b) applying the solution obtained from step (a) to an anion exchange chromatography resin; c) eluting the flavivirus viral particles from the anion exchange chromatography resin; d) subjecting the eluent from step (c) to TFF; and e) recovering the purified flavivirus viral particles (p. 7, lines 13-21; Mundle claim 1). Thus, Mundle’s methods do not require an endonuclease step, and the host cell DNA would inherently be removed by the anion exchange chromatography step disclosed by Mundle. Further, Applicant’s argument is not commensurate in scope with the claims, as only new claims 21 and 22 specify that the method does not include any step of endonuclease treatment, otherwise, both independent claims 1 and 9 are methods comprising the active steps. Furthermore, the increased robustness Applicant argues above would have been observed by the obvious method if enzyme removal is all that is required for increased robustness.
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).
It is apparent to the examiner that a person of ordinary skill of the art, performing the method disclosed by Mundle would achieve flavivirus purification without an endonuclease treatment step, because naked DNA is highly negatively charged and will elute very differently from the viral particles during anion exchange chromatography. Regardless of why the prior art is doing something, the reason they are doing it does not have to be Applicant's reasons for doing it. And the obvious method just has to comprise the same steps, it does not have to have them for the same purposes as Applicant's. The reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. See, e.g., In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006).
Applicant’s argument that it could not be readily expected that purification strategies developed for West Nile virus-based constructs would produce the same results for Dengue virus-based constructs is not persuasive because Mundle discloses that additional enveloped viruses suitable for purification using the methods include, but are not limited to, viruses of the genus flavivirus such as Dengue fever virus (p. 11, para. 2). Thus, a person of ordinary skill in the art would have an expectation that the method would be applicable to Dengue virus and have motivation to apply that approach to Dengue virus purification.
The Examiner wishes to inform applicants of the following guidelines pertaining to arguments that mirror supported claims or facts but are not founded on a factual basis.
In the MPEP:
MPEP §2145 Consideration of Applicant's Rebuttal Arguments:
(I) ARGUMENT DOES NOT REPLACE EVIDENCE WHERE EVIDENCE IS NECESSARY
Attorney argument is not evidence unless it is an admission, in which case, an examiner may use the admission in making a rejection. See MPEP § 2129 and§ 2144.03 for a discussion of admissions as prior art.
The arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602,145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997) (“An assertion of what seems to follow from common experience is just attorney argument and not the kind of factual evidence that is required to rebut a prima facie case of obviousness.”). See MPEP § 716.01(c) for examples of attorney statements which are not evidence and which must be supported by an appropriate affidavit or declaration.
MPEP §716.01 (c) Probative Value of Objective Evidence
I. TO BE OF PROBATIVE VALUE, ANY OBJECTIVE EVIDENCE SHOULD BE SUPPORTED BY ACTUAL PROOF
Objective evidence which must be factually supported by an appropriate affidavit or declaration to be of probative value includes evidence of unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the applicant. See, for example, In re De Blauwe, 736 F.2d 699, 705, 222 USPQ191, 196 (Fed. Cir. 1984) (“It is well settled that unexpected results must be established by factual evidence.” “[A]ppellants have not presented any experimental data showing that prior heat-shrinkable articles split. Due to the absence of tests comparing appellant’s heat shrinkable articles with those of the closest prior art, we conclude that appellant’s assertions of unexpected results constitute mere argument.”). See also In re Lindner, 457 F.2d 506, 508, 173 USPQ 356,358 (CCPA 1972); Ex parte George, 21 USPQ2d 1058(Bd. Pat. App. & Inter. 1991).
II. ATTORNEY ARGUMENTS CANNOT TAKE THE PLACE OF EVIDENCE
The arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602,145 USPQ 716, 718 (CCPA 1965). Examples of attorney statements which are not evidence and which must be supported by an appropriate affidavit or declaration include statements regarding unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the applicant.
See MPEP § 2145 generally for case law pertinent to the consideration of applicant’s rebuttal arguments.
III. OPINION EVIDENCE
Although factual evidence is preferable to opinion testimony, such testimony is entitled to consideration and some weight so long as the opinion is not on the ultimate legal conclusion at issue. While an opinion as to a legal conclusion is not entitled to any weight, the underlying basis for the opinion may be persuasive. In re Chilowsky,306 F.2d 908, 134 USPQ 515 (CCPA 1962) (expert opinion that an application meets the requirements of 35U.S.C. 112 is not entitled to any weight; however, facts supporting a basis for deciding that the specification complies with 35 U.S.C. 112 are entitled to some weight); In re Lindell, 385 F.2d 453, 155 USPQ 521 (CCPA 1967)(Although an affiant’s or declarant’s opinion on the ultimate legal issue is not evidence in the case, “some weight ought to be given to a persuasively supported statement of one skilled in the art on what was not obvious to him.” 385 F.2d at 456, 155 USPQ at 524 (emphasis in original)).
Presently and in view of the guidance from MPEP §2145 and §716 above, Applicants statements regarding that it could not be readily expected that purification strategies developed for West Nile virus-based constructs would produce the same results for Dengue virus-based constructs have not been found convincing.
Wiggan discloses that combinations of excipients, such as trehalose, albumin, and polaxamer 407, stabilize live-attenuated flavivirus vaccine candidates. It would have been obvious to one of ordinary skill in the art to add excipients to flavivirus compositions to increase their stability at each step of processing. Additionally, purification would have occurred via anion exchange chromatography even if the non-ionic surfactant, sugar, and protein (or specific claimed non-ionic surfactant, sugar, and protein) were present in the buffer, because the host cell DNA is highly negatively charged and would have interacted with the anion exchange resin regardless of the presence of the excipients.
Regarding Applicant’s alleged surprising and unexpected result, the results are not commensurate in scope with the claims. Whereas the claims encompass generic non-ionic surfactants, sugars, and proteins, Table 2, which Applicant refers to demonstrate unexpected and surprising results, only examines reduction in host cell DNA concentration using one composition (FTA).
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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
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