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 6/16/2026 is acknowledged.
Claims 1-5, 7-17, 19-21, and 23 are under examination on the merits.
Information Disclosure Statement
The Information Disclosure Statement (IDS) submitted on 6/2/2026 is in compliance with 37 CFR 1.97. Accordingly, the reference listed in the IDS is being considered by the examiner.
Withdrawn Objections
The following objections are hereby withdrawn, due to Applicant’s amendment submitted 6/16/2026:
Claim objections: Claims 1-4 and 13-16 for minor informalities.
Withdrawn Rejections
The following rejections are hereby withdrawn, due to Applicant’s amendment submitted 6/16/2026:
35 U.S.C. §112(b): claim 12, for previously including the limitation “wherein repeatedly increasing the at least one of the temperature and the incubation period comprises controlling a second thermal energy device”.
Maintained Rejections
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, 7-17, 19-21, and 23 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.
Applicant’s arguments have been carefully considered but are found unpersuasive.
Applicant presents the following arguments:
Applicant notes that none of the terms “cell culture,” “virions,” “trypsin digestion,” and “trypsinization” are recited in the claims. The Office’s reliance on these terms to support a an indefiniteness rejection is therefore misplaced, and only serves to obfuscate a proper analysis of the claim language under 35 USC 112(b). The claim language must be considered as a whole, and in this regard, Applicant asserts the language is not indefinite.
Each of the independent claims 1 and 13 require "generating virus ions from the virus preparation." With respect to the limitation "increasing at least one of a temperature . . . of at least one of the virus preparation and the generated virus ions" recited in independent claims 1 and 13, this language clearly requires, as it relates to temperature, increasing the temperature of the previously recited virus preparation itself or of the previously recited virus ions that have been generated from the virus preparation.
With respect to the limitation "increasing at least one of an incubation period at the increased temperature of at least one of the virus preparation and the generated virus ions" recited in independent claims 1 and 13, this language clearly requires, as it relates to incubation period, increasing the incubation period of the previously recited virus preparation, or increasing the incubation period of the previously recited virus ions. Each of the independent claims 1 and 13 further require "measuring mass-to-charge ratios and charge magnitudes of at least some of the generated ions at each increase of the at least one of the temperature and the incubation period." Again as it relates to incubation period, this language clearly requires the mass-to-charge ratios and charge magnitudes of the generated ions to occur at each increase of the incubation period, i.e., after the incubation period has been increased. Thus, the language of each of claims 1 and 13 clearly recites what is being increased in incubation period, and when the incubation period increase is being carried out relative to the measurement of mass- to-charge ratios and charge magnitudes, and therefore each of the independent claims 1 and 13 are not indefinite with respect to the "increasing ... incubation period" limitation.
Applicant’s arguments are unpersuasive because:
The terms “cell culture,” “virions,” “trypsin digestion,” and “trypsinization” do not have to be recited in the claims, they were used for illustrative purposes in applying the BRI and demonstrating the indefiniteness of the claims.
As demonstrated by Applicant’s words, the increased temperature may interpreted to be of the virus preparation or the generated virus ions. The first step is either in culture or in a machine, it is unclear which is required by the instant claims. It is not appropriate for a method claim to have such enormously different meanings, because a person having ordinary skill in the art, and the patent system in general, expect each step to have a clear relationship to each other and understood/envisioned order. In the instant case of interpretations, those two things (the increased temperature is of the virus preparation or the generated virus ions) are too different for the claims’ scope to be definite.
The claims should make clear where the temperature is changing, so a person of ordinary skill in the art can properly interpret the results of the method and what aspect is being optimized (e.g., machine temperature or culture temperature).
Regarding the incubation period: as demonstrated by Applicant’s words, the period can be of the preparation or the virus ions. The first step is either in culture or in a machine, it is unclear which is required by the instant claims. It is not appropriate for a method claim to have such enormously different meanings, because a person having ordinary skill in the art, and the patent system in general, expect each step to have a clear relationship to each other and understood/envisioned order. In the instant case of interpretations, those two things (the increased incubation period is of the virus preparation or the generated virus ions) are too different for the claims’ scope to be definite.
The claims should make clear where the incubation period is changing, so a person of ordinary skill in the art can properly interpret the results of the method and what aspect is being optimized (e.g., machine temperature or culture temperature).
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.
Claims 1-5, 7-17, 19-21, and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Fuerstenau, et al. (Angew Chem Int Ed Engl. 2001 Feb 2;40(3):541-544) in view of Kukreja, et al. (J Virol 2014 Dec;88(24):14105-15. Epub 2014 Sep 24), Horowitz, et al. (J Virol 2013 Mar;87(6):2994-3002), Tai, et al. (Mol Ther Methods Clin Dev 2018 Feb 13;9:130-141), Li et al. (Current Pharmaceutical Biotechnology, 2017, 18, 638-647), and Kirkpatrick et al. J Proteome Res. 2017 Sep 1;16(9):3255-3265).
Applicant’s arguments have been carefully considered but are found unpersuasive.
Applicant presents the following arguments:
Applicant respectfully traverses the 35 U.S.C. §103 rejection of claims 1-5, 7-17, 19-21, and 23 as being obvious over Fuerstenau in view of Kukreja, Horowitz, Tai, Li, and Kilpatrick because no single one or combination of these references discloses each and every limitation of each of the independent claims 1 and 13, and therefore no single one or combination of these references can support a prima facie obviousness rejection under 35 U.S.C. §103. Moreover, as each of the claims 2-5, 7-12, 14-17, 19-21, and 23 depends from claim 1 or claim 13, and therefore only adds further limitations, no single one or combination of the above-noted references can support a prima facie obviousness rejection under 35 U.S.C. §103 for the same reason.
With respect to Furstenau, the Office admits that although Furstenau discloses "mass spectrometry of intact viruses," Furstenau fails to teach "reducing heterogeneity of a virus preparation by increasing temperature or incubation period, determining a mass spectrum at each increase of temperature or incubation period, and determining based on mass spectrum optimum temperature and incubation period to minimize or reduce heterogeneity of the virus preparation without aggregation of virus capsids in the virus preparation." In other words, Furstenau fails to teach most of the limitations of each of the independent claims 1 and 13.
Kukreja describes incubating sample mixtures at various temperatures (see, e.g., pg. 14107, last paragraph - pg. 14108, first paragraph), but is completely silent as to any effect such actions have on heterogeneity of the mixture; more specifically, Kukreja is silent as to determining, based on mass-to-charge ratio and charge magnitude measurements, optimum ones of temperature and incubation period which together minimize, or at least reduce, heterogeneity of the mixture without aggregation of virus capsids in the mixture, as required by the language of claims 1 and 13.
Horowitz similarly describes incubating sample mixtures at various temperatures (see, e.g., pg. 2996, last paragraph, left col. - last paragraph, right col.), but, like Kukreja, is completely silent as to any effect such actions have on heterogeneity of the mixture, such as determining, based on mass-to-charge ratio and charge magnitude measurements, optimum ones of temperature and incubation period which together minimize, or at least reduce, heterogeneity of the mixture without aggregation of virus capsids in the mixture, as required by the language of claims 1 and 13. In fact, Horowitz fails to mention any mass-to-charge ratio and charge magnitude measurements of ions.
Li describes temperature vs. size studies of an HSV-2 virus vaccine, and describes a mathematical model for predicting temperature-induced aggregation of HSV particles (see, e.g., section 3.2, pgs. 643-646). However, like Kukreja and Horowitz, Li is completely silent as to any effect that their studies may have on heterogeneity of the virus vaccine, such as determining, based on mass-to-charge ratio and charge magnitude measurements, optimum ones of temperature and incubation period which together minimize, or at least reduce, heterogeneity of the virus vaccine without aggregation of virus capsids in the mixture, as required by the language of claims 1 and 13. In fact, like Horowitz, Li fails to mention any mass-to-charge ratio and charge magnitude measurements of ions. Moreover, the subject matter of claims 1 and 13 is directed to avoiding aggregation as determined based on mass spectra, rather than predicting temperature-induced vibration as taught by Li.
Tai describes a single molecule sequencing approach to profile AAV genomes. Tai fails to describe heating and/or incubating of sample preparations, or of measuring mass-to-charge ratios and charge magnitudes of sample ions, or of determining based on mass-to-charge ratio and charge magnitude measurements, optimum ones of temperature and incubation period which together minimize, or at least reduce, heterogeneity of the virus vaccine without aggregation of virus capsids in the mixture, all as required by the language of claims 1 and 13.
Kilpatrick describes a process for optimizing the signal-to-noise ratio of a mass spectrometer to provide for improved detection of post-translational modifications (PTMs) during LC-MS of intact proteins. Nowhere does Kilpatrick describe such processes as having any effect on heterogeneity of the proteins, such as determining, based on mass-to-charge ratio and charge magnitude measurements, optimum ones of temperature and incubation period which together minimize, or at least reduce, heterogeneity of the proteins, as required by the language of claims 1 and 13.
From the foregoing, it should be apparent that no single one or combination of Fuerstenau, Kukreja, Horowitz, Tai, Li, and Kilpatrick teach all of the limitations of each of the independent claims 1 and 13. Indeed, as described above, none of these references describes determining, based on measured mass spectra, optimum ones of temperature and the incubation period which together minimize, or at least reduce, the heterogeneity of a virus preparation without aggregation of virus capsids in the virus preparation, as required by all of the claims 1-5, 7-17, 19-21, and 23, and no reference of record can cure this deficiency in the cited references. Accordingly, none of the references of record can support a prima facie obviousness rejection of any of claims 1- 5, 7-17, 19-21, and 23.
Applicant’s arguments are unpersuasive because:
The examiner acknowledges the individual deficiencies of the cited references pointed out by Applicant.
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).
However, the rejection is under 35 U.S.C. §103, and for the reasons of record, the references properly support a prima facie case of obviousness. The combination of these references render obvious each and every limitation of the claims.
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.
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/JEFFREY MARK SIFFORD/Examiner, Art Unit 1671 /Michael Allen/Supervisory Patent Examiner, Art Unit 1671
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