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 .
Response to Amendment
The amendment filed 26 June 2026 in which claims 1-4, 20, and 42 were amended and claim 37 was cancelled has been entered.
Claims 1-5, 20-22, 33-35, 40, and 42-43 are under examination on the merits.
Specification
(Previous objection withdrawn) Applicant’s amendment to the Specification filed 26 June 2026 has overcome the objection previously set forth in the Non-Final Office Action mailed 06 March 2026.
Claim Rejections - 35 USC § 112(b)
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(Previous rejection, withdrawn as to claims 2-4, 20, 37, and 42 due to amendment of claims 2-4, 20, and 42 and cancellation of claim 37). Claims 2-4, 20, 37, and 42 were 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 amendment of claims 2-4, 20, and 42 and cancellation of claim 37 submitted 26 June 2026 has overcome the rejection previously set forth in the Non-Final Office Action mailed 06 March 2026.
(New rejection necessitated by amendment to claim 1). Claims 1-5, 20-22, 33-35, 40, and 42-43 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.
It is unclear, in claim 1, when the temperature is switched from the first to the second temperature and for which infection (first or second) the temperature is switched. Claim 1 is indefinite because the infection(s) on which the switching occurs is not clearly defined as well as when the switching occurs, i.e. during infection, before infection, after infection. The claim does not clearly define the parameters for switching temperatures during the method, rendering the claim indefinite.
The dependent claims do not add additional clarity and, therefore, are also indefinite.
For the purposes of compact prosecution and applying prior art the “first temperature” refers to a temperature at which the cell populations cultured prior to addition of adenovirus to the cell population and the “second temperature” is the lower infection temperature (Specification pg. 16).
It is noted any interpretation of the claims set forth above does not relieve Applicant of the responsibility of responding to this rejection. If the actual interpretation of the claims is different than that posited by the Examiner, additional rejection and art may be readily applied in a subsequent Office action.
Claim Rejections - 35 USC § 112(d)
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.
(New rejection, necessitated by amendment to claim 1). Claim 5 is 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 5 does not further limit the claim as all the limitations in claim 5 are originally claimed in claim 1 and all the limitations in claim 5 are also required by claim 1.
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
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, withdrawn as to claims 1-3, 20, 22, 33-35, 37, 40, and 42-43 due to amendments to claim 1 and 20 and cancellation of claim 37). Claims 1-3, 20, 22, 33-35, 37, 40, and 42-43 were rejected under 35 U.S.C. 103 as being unpatentable over Fedosyuk in view of Faisst. Applicant’s amendment of claim 1 submitted 26 June 2026 has rendered the rejection previously set forth in the Non-Final Office Action mailed 06 March 2026. Applicants amendment of claims 1 and 20 submitted 26 June 2026 has added new limitations to the claim rendering the rejection previously set forth in the Non-Final Office Action mailed 06 March 2026 moot and necessitating a new rejection.
(Previous rejection, withdrawn as to claims 4-5 due to amendment to claim 1). Claims 4-5 were rejected under 35 U.S.C. 103 as being unpatentable over Fedosyuk and Faisst and further in view of Genemedi. Applicant’s amendment of claim 1 submitted 26 June 2026 has added new limitations to the claim rendering the rejection previously set forth in the Non-Final Office Action mailed 06 March 2026 moot and necessitating a new rejection.
(Previous rejection, withdrawn as to claim 21 due to amendment to claim 1). Claim 21 was rejected under 35 U.S.C. 103 as being unpatentable over Fedosyuk and Faisst and further in view of Genzel. Applicant’s amendment of claim 1 submitted 26 June 2026 has added new limitations to the claim rendering the rejection previously set forth in the Non-Final Office Action mailed 06 March 2026 moot and necessitating a new rejection.
(New rejection necessitated by amendment to claims 1 and 20). Claims 1-5, 20, 22, 33-35, 40, and 42-43 are rejected under 35 U.S.C. 103 as being unpatentable over Fedosyuk and further in view of Faisst, Genemedi, and Jardon, et al. (Biotechnol Prog. 2003 Jan-Feb;19(1):202-8., hereinafter “Jardon”).
Regarding claims 1 and 5, Fedosyuk teaches a method of producing an adenovirus for use in a vaccine (pg. 6951, Abstract), the method comprising: (a) adding adenovirus to a cell population in culture (pg. 6953, column 1); (b-c) culturing the cells under conditions that allow for infection and viral replication (pg. 6953, column 1 and Figure 1); and (d) harvesting the adenovirus (pg. 6954, column 2). Fedosyuk does not teach that adenovirus infection occurs at an MOI insufficient for infection of all the cells in culture.
However, Faisst teaches methods for propagating viruses including adenoviruses and further teaches that adenovirus preparations may contain up to 1000 defective particles per infectious virion and in order to generate as few defective particles as possible, adenovirus infection should occur at an MOI of 0.01 (1 infectious viral particle per 1000 cells) (pg. 1411, column 2).
It would have been prima facie obvious to one or ordinary skill in the art before the effective filing date of the invention to have combined the teachings of Fedosyuk for a method of producing an adenovirus for use in a vaccine and the teachings of Faisst for infecting cells with a low MOI of adenovirus. Faisst provides motivation by teaching that adenovirus preparations may contain up to 1000 defective particles per infectious virion and in order to advantageously generate as few defective particles as possible, adenovirus infection should occur at an MOI of 0.01 (1 infectious viral particle per 1000 cells) (pg. 1411, column 2). One of ordinary skill would have had a reasonable expectation of success in combining Fedosyuk and Faisst because the both teach adenovirus propagation.
Fedosyuk and Faisst do not teach a first and second infection. However, Genemedi teaches adding adenovirus-containing supernatant into freshly seeded cells to amplify adenovirus (pg.7) It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to repeat the infection steps taught by Fedosyuk and Faisst after a first round of infection in order to obtain the same and predictable benefit of amplification of adenoviruses as taught by Genemedi (pg. 7).
Fedosyuk, Faisst, and Genemedi do not teach switching temperatures from a higher temperature, for cell culturing, to a lower temperature for adenovirus infection. However, Jardon teaches culturing cells at 37°C (pg. 203, column 1) and then changing the temperature to 35°C for adenovirus infection to increase virus yield (abstract).
It would have been prima facie to one of ordinary skill in the art before the effective filing date of the invention to have combined the teachings of Fedosyuk, Faisst, and Genemedi for a method of producing adenovirus for use in a vaccine with the teachings of Jardon that infecting at a lower (35°C) temperature increase adenoviral production. Jardon provides motivation by teaching that infecting at 35°C instead of 37°C increased adenovirus yield 3-fold (abstract). One of ordinary skill in the art would have had a reasonable expectation of success in combining the teachings of Fedosyuk, Faisst, Genemedi, and Jardon because they all teach adenovirus infection.
Regarding claim 2, Faisst teaches infecting cells with an MOI of 0.1 of adenovirus (pg. 1411, column 2).
Regarding claim 3, Fedosyuk teaches infecting cells immediately after cell seeding (pg. 6953, column 1).
Regarding claim 4, Fedosyuk and Faisst do not teach infecting cells 24 hours after cell seeding. However, routine optimization of the time between seeding and infection taught by Fedosyuk would have led to the claimed time period of 24 hours because Genemedi teaches that cell confluency should be 50-70% at the time of infection and that the time that takes and the number of cells seeded is a parameter that requires optimization to achieve the best results (pg. 9). The person of ordinary skill in the art would have found it obvious to optimize the time period between cell seeding and infection to achieve the desired cell density by starting at the time period taught by Fedosyuk because Genemedi teaches that cell confluency should be 50-70% at the time of infection and that the time that takes and the number of cells seeded is a parameter that requires optimization to achieve the best results (pg. 9).
It would have been further be obvious that the time period between cell seeding and viral infection is clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been customary for an artisan of ordinary skill to determine the optimal time period of between cell seeding and infection needed to achieve the desired results.
Regarding claim 20, Fedosyuk teaches culturing the cells in a 3L bioreactor (pg. 6953, column 1). Fedosyuk does not teach culturing the cells in a 2000 liter of bigger bioreactor. However, routine optimization of the infection parameters, including bioreactor size, taught by Fedosyuk would have led to scaling up adenoviral production by increasing the bioreactor size. Fedosyuk provides motivation by teaching that these methods can be used for adenoviral production, and the volumetric yield can be increased by increasing bioreactor size (pg. 6957, column 2). The person of ordinary skill in the art would have found it obvious to increase the size of the bioreactor taught by Fedosyuk because the bioreactor size would need to be increased to volumetric yield.
Regarding claim 22, Fedosyuk teaches adding L-glutamine to the cell media (pg. 6952, column 2).
Regarding claims 33-35, Fedosyuk teaches that the cells are HEK293 T-rex cells (pg. 6952, column 2).
Regarding claims 40 and 42-43, Fedosyuk teaches that the virus is ChAdOx2 and ChAd63 (pg. 6952, column 2).
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill in the art before the effective filing date, especially is absence of evidence to the contrary.
(New rejection, necessitated by amendment to claim 1) Claim 21 is rejected under 35 U.S.C. 103 as being unpatentable over Fedosyuk, Faisst, Genemedi, and Jardon as applied to claims 1-5, 20, 22, 33-35, 40, and 42-43 above, and in further view of Genzel.
As described above, claims 1-5, 20, 22, 33-35, 40, and 42-43 were rendered prima facie obvious over Fedosyuk, Faisst, Genemedi, and Jardon.
Regarding claim 21, Fedosyuk, Faisst, Genemedi, and Jardon do not teach not replacing the cell media or adding media to the cell culture. However, Genzel teaches methods of serum-free viral production to avoid washing steps and medium exchange and further teaches that not adding or replacing media during infection can simplify the infection process and reduced sterility issues during infection and cell culturing (Abstract).
It would have been prima facie obvious to one or ordinary skill in the art before the effective filing date of the invention to have combined the teachings of Fedosyuk, Faisst, Genemedi, and Jardon for a method of producing an adenovirus for use in a vaccine and the teachings of Genzel for not replacing or adding cell media after infection. Genzel provides motivation by teaching that not adding or replacing media during infection can simplify the infection process and reduced sterility issues during infection and cell culturing (Abstract). One of ordinary skill would have had a reasonable expectation of success in combining Fedosyuk, Faisst, Genemedi, Jardon, and Genzel because the all teach viral propagation.
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill in the art before the effective filing date, especially is absence of evidence to the contrary.
Response to Arguments
Applicant contends on page 7 of the Remarks submitted 26 June 2026 that the term “about” is defined in the Specification on page 33 lines 28-33.
In response: The definition given for about gives a broad range of “exemplary” degrees of error. The term “about” is not clearly defined. However, applicant removed then term about from the claims, therefore, the argument and rejection are moot.
Applicant contends on pages 8-9 of the Remarks submitted 26 June 2026 that Fedosyuk does not teach first or second infection fractions nor any temperature switch, while Faisst does teach infection with a low MOI, Faisst does not teach temperature switching, and one of ordinary skill in the art would not be lead to the combination of a low-MOI cascade infection and temperature shifting and that Gezel does not fix any of the previous deficits. The applicant further contends that assuming the Examiner’s arguments were true, that the results achieved by the applicant were surprising and unexpected.
In response: Applicant’s arguments with respect to claim 1 have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument. Applicant added new limitations, including multiple rounds of infection and temperature switching which are not taught by the previous art and required a new rejection to reject the new limitations, therefore the arguments are moot. Furthermore, it is not unexpected that infection of cells with a low MOI of adenovirus would lead to an increased yield. To rebut Applicant’s argument, Yamada, et al. (Cytotechnology. 2009 Apr;59(3):153-60., NPL-IDS, filed, 06/30/2024, hereinafter “Yamada”) evidences that infecting 293 cells with an adenovirus vector at an MOI of 0.001 which yield a 2.7-fold higher adenovirus yield that infecting with a high MOI (10) (abstract).
Conclusion
NO CLAIMS ARE ALLOWED
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Cassandra Senn Grizer whose telephone number is (571)272-2292. The examiner can normally be reached M-Th 0630 - 1700 ET.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Thomas J. Visone can be reached at 571-270-0684. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/CASSANDRA SENN GRIZER/Examiner, Art Unit 1672
/THOMAS J. VISONE/Supervisory Patent Examiner, Art Unit 1672
Prosecution Insights