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 .
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
This Action is in response to the papers filed on 11/12/2025. Claims 1, 3-8, 10, and 12-21 are pending. Claims 1, 15, 20 and 21 are independent claims.
Applicant amended claims 1, 2, and 12, cancelled claims 2, 9, and 11, and added claims 20 and 21 by Applicant’s amendment filed on 11/12/2025. Applicant's election without traverse of Group I, which included claims 1-16 (claims 2, 9 and 11 now cancelled), and election of species for Group I, SEQ ID NO: 11 for claim 8, SEQ ID NO: 11 for claim 10, 13, and 14, in the reply filed on 04/24/2025 was previously acknowledged.
Claims 13-14 were withdrawn from further consideration pursuant to 37 CPR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Claims 17-19 were withdrawn from further consideration pursuant to 37 CPR 1.142(b) as being drawn to a nonelected subject matter, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 04/24/2025. This restriction was previously made final.
The terminal disclaimer filed on 11/10/2025 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of the full statutory term of U.S. Patent No. 11,376,290 has been reviewed and is accepted. The terminal disclaimer has been recorded.
Therefore, claims 1, 3-8, 10, 12, 15-16, and 20-21 are subject to examination to which the following grounds of rejection are applicable.
Priority
The instant application is a CON of 16/528,689 filed 08/01/2019, PAT 11376290.
16/528,689 is a CIP of 16/352,806 filed 03/13/2019 ABN, 16/352,806 is a CIP of 62/643,166
filed 03/14/2018.
Thus, the earliest possible priority for the instant application is 03/14/2018.
Withdrawn Objections/Rejections in response to Applicants’ arguments or amendmentsObjections – Specification
The objection to the specification is withdrawn in view of the amendments in the response filed on 11/12/2025.
Applicant’s arguments with regard to a withdrawn objection/rejection are moot.
Double Patenting Rejection
The rejection of claims 1-12, 15, and 16 on the grounds of rejection over U.S. Pat. No. 11/376,290 B2 is withdrawn in view of Applicants’ terminal disclaimer over U.S. Patent No. 11,376,290 filed on 11/10/2025.
Applicant’s arguments with regard to a withdrawn objection/rejection are moot.
Maintained and modified rejections in response to Applicants’ arguments or amendments
Claim Rejections - 35 USC § 112(b)
Claim 12 remains rejected and new claim 20 is 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 applicant regards as the invention.
This rejection has been modified as necessitated by amendment of the claims in the response filed 11/12/2025.
Claims 12 and 20 recite the trademark pVAX1 vector (Thermofisher (pVAX1™ User Guide, 2012)). If the trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of the 35 U.S.C. 112, second paragraph. Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. In fact, the value of a trademark would be lost to the extent that it became descriptive of a product, rather than used as an identification of a source or origin of a product. Thus, the use of a trademark or trade name in a claim to identify or describe a material or product would not only render a claim indefinite, but would also constitute an improper use of the trademark or trade name.In the present case, the trademark/trade name is used to identify/describe types of vectors use in the development of DNA vaccines, accordingly, the identification/description is indefinite.
Claim Rejections - 35 USC § 103
Claim(s) 1, 3-7 and 15remain rejected and claim 16 is newly rejected under 35 U.S.C. 103 over Kim et al. (Kim DS et al., Gene Ther. 2012) in view of Lee et al. (OS9617344 B2, of record) and Fountzilas et al. (Fountzilas C et al., Oncotarget., 2017, of record) and further in view of Massilamany et al. (Massilamany et al., PLOS ONE., 2015, of record).This rejection has been modified as necessitated by amendment of the claims in the response filed 11/12/2025.
Amended Claim 1 recites, “A recombinant oncolytic virus, comprising: a genome of an oncolytic virus and an exogenous DNA sequence inserted into the genome, wherein; the oncolytic virus is Coxsackievirus B3 strain comprising base mutations of T97C, G1180A Tl654C, Tl756C, G2276A, A2685C, G2690A, C3120A, A3231G, G4327A, T5088C, A5270G, C7026T, and/or G7192A: the exogenous DNA sequence is inserted between 5' untranslated region (5'UTR) and VP4 of the genome of the oncolytic virus and the exogenous DNA sequence is adapted to express a basic peptide fragment and to increase an environmental pH in a host infected by the recombinant oncolytic virus.”
Regarding claims 1, 3, and 15-16, Kim et al. teach CVB3 can be used as an effective viral delivery vector for gene therapy and also teaches construction of a recombinant CVB3 genome expressing FGF2 using an infections cDNA clone of CVB3 (Abstract). Kim teaches “The sequence encoding FGF2 was inserted immediately upstream from the gene encoding the viral VP4 capsid protein.” (Materials and Methods, 2nd Paragraph).
Kim et al. does not specifically teach the use of CVB3 as an oncolytic virus. However, CVB3 is well known in the art to be inherently cytolytic and has a documented history for use as an oncolytic viral vector in cancer therapy as demonstrated by Fountzilas et al. Fountzilas et al. is a review article that describes the state of the art of oncolytic virotherapy. Fountzilas et al. discusses many types of oncoviruses undergoing human clinical trials and particular features of each type. Fountzilas et al. describe both oncolytic adenovirus (Table 1A) and oncolytic coxsackievirus B3 (Table 2B) can successfully be used to treat cancer.
Kim et al. does not teach CVB3 virus engineered to express basic peptides or that the CVB3 contains base mutations as recited in claim 1.
Lee et al. teaches "a method of preventing and/or treating cancer, comprising administering a conjugate comprising a fusion protein and a p16 protein variant to a subject" (Column 22, lines 1-3). Lee et al. teaches "providing a nucleic acid encoding a fusion protein comprising a hydrophobic peptide, basic peptide and bioactive substance" (Column 20, lines 1-3). Lee et al. teaches a "recombinant vector, the polynucleotide encoding the protein conjugate" The fusion protein may include multiple bioactive peptides or proteins known to possess anti-cancer capacity (Column 11, 1st Paragraph). Moreover, Lee et al teaches multiple basic peptide sequences, including those containing lysine and arginine, such as RKRK (SEQ ID NO: 18), (Column 7, Line 41). Lee teaches “Some of the basic peptides have been known to have a nuclear membrane penetrating activity; however, none of them has been known to have a cell membrane penetrating activity. In the present disclosure, the basic peptide is fused (e.g., linked) with a hydrophobic peptide (e.g., via a peptide bond), to produce a fusion peptide, thereby considerably increasing the cell membrane penetrating effect of the hydrophobic peptide or the fusion peptide.” (Column 7, 3rd full paragraph).
It would have been obvious to adapt the CVB3 of Kim to insert a basic peptide fragments according to Lee to incorporate a polynucleotide taught by Lee encoding a fusion protein comprising a basic peptide containing lysine-arginine tumor suppressor p16 to produce a cancer treatment having an enhanced cell membrane penetrating effect.
Regarding the base mutations recited in claim 1, Massilamany teaches many of the mutations listed in claim 1, such as A4327G and indicate that these are responsible for attenuation of the coxsackievirus B3 (Pg. 6, Table 2.).
Further, Massilamany teaches attenuation of coxsackievirus B3 via mutation, such as A4327G, would reduce occurrence of adverse events seen in WT coxsackievirus administration (Pg. 9, 1st incomplete paragraph).
It would have been obvious to a person of ordinary skill in the art at the time of the application to have modified the CVB3 as taught by Kim et al. to incorporate a polynucleotide taught by Lee encoding a fusion protein comprising a basic peptide containing lysine-arginine tumor suppressor p16 to produce a cancer treatment acting through tumor cell senescence. Moreover, a person having ordinary skill in the art would recognize the value of modifying the virus of Kim and Lee by incorporating a mutation shown to attenuate the oncolytic coxsackie virus B3 by using a mutation taught by Massilamany, such as A4327G, to reduce adverse events caused by WT coxsackievirus resulting is a more effective and less harmful therapeutic.
There would be a reasonable expectation of success as it would have been a matter of combining known prior art elements according to known methods to yield predictable results. All of the claimed elements were known in the prior art and one skilled in the art could have combined the element as claimed by known methods with no change in their respective functions, and the combination would have yielded predictable results to one of ordinary skill in the art at the time of the invention. The skilled artisan would have had a reasonable expectation of success in combining the teachings of Lee, Kim, and Massilamany because the molecular biology required to produce a recombinant oncolytic virus expressing a fusion protein had been practiced prior to the filing of the instant application.
Therefore, the oncolytic virus as taught by Lee, Kim, and Massilamany would have been prima facie obvious over the oncolytic virus of the instant application.
Regarding the functional limitation of claim 1 directed to "the exogenous DNA sequence being adapted to express a basic peptide fragment and to increase an environmental pH in a host infected by the recombinant oncolytic virus," the examiner has pointed to the fusion protein of Lee et al. that teaches including the cell membrane penetrating peptide, RKRK. Therefore, the exogenous DNA sequence of the adenovirus is adapted to express a basic peptide fragment. This structural limitation is met. A person of ordinary skill in the art of acid/base/pH chemistry, readily understands that increasing the presence of basic molecules in an aqueous environment generally increases the environmental pH. While Lee et al did not propose their basic peptides as being used to alter the pH of the tumor cell's environment, this is not necessary for the basis of a prima facie case of obviousness, when Lee et al. proposes the RKRK basic peptide for another use, namely as a cell membrane penetrating peptide. Accordingly, it would have been obvious for a person of ordinary skill that this functional limitation is also met and implicitly present in Lee's virus genome comprising an exogenous DNA sequence expressing a basic peptide fragment. Furthermore, MPEP 2112.01(11) recites that "products of identical chemical composition cannot have mutually exclusive properties. A chemical composition and its properties are inseparable."
Similarly, the limitations of claim 3 directed to "wherein the environmental pH in the
host infected by the recombinant oncolytic virus is increased by 0.4 to 0.6," would seem to be obvious due to the MPEP 2112.01(11) guidance which recites that "products of identical chemical composition cannot have mutually exclusive properties. A chemical composition and its properties are inseparable." Regarding claims 4-7, the teachings of Lee, Kim, Fountzilas and Massilamany above render obvious the virus of claim 1. Moreover, Lee et al teaches multiple basic peptide sequences, including those containing lysine and arginine, such as RKRK (Column 7, line 41). This reads on the limitations for the size of the basic peptide fragment recited in claim 4, the basic amino acid % requirements recited in claim 5-6, and the arginine and lysine selections in claim 7.
Regarding the combination therapy of claim 16, requiring both an oncolytic virus and a
checkpoint inhibitor, Fountzilas et al. teach "[t]here are preclinical data for synergy between
OVs [oncoviruses] and immune checkpoint inhibition" (page 102625, Column2, 2nd Paragraph).
Accordingly, there is explicit teaching, suggestion, and motivation to combine checkpoint
inhibitor with an oncolytic virus.
Claims 8 and 10 remain rejected and claim 21 is newly rejected under 35 U.S.C. 103 as being unpatentable over Kim et al. (Kim DS et al., Gene Ther. 2012) in view of Lee et al. (OS9617344 B2, of record) and Fountzilas et al. (Fountzilas C et al., Oncotarget., 2017, of record) and further in view of Massilamany et al. (Massilamany et al., PLOS ONE., 2015, of record) as applied to claim 1 and in further view of Castillo et al (US 10010613 B2, of record) as evidenced by (Zhang P et al., Cell., 2018, of record).
Regarding claims 8, 10, and 21 Kim, Lee, Fountzilas, and Massilamany render obvious the oncolytic virus, as iterated above in the 103 rejections, the content of which is incorporated herein, in its entirety. In particular, Lee teaches various basic peptides that can be used to make therapeutic fusion proteins, including cell membrane penetrating peptides such as RKRK, KKKR, KKKKKR or RRRRR.
However, the teachings of Kim, Lee, Fountzilas, and Massilamany do not identify the claimed sequence, KRRK (selected species of SEQ ID NO: 11), as being a cell membrane penetrating peptide.
Castillo cures these deficiencies as they teach the sequence of the basic peptide of the instant application KRRK (Column 104, Lines 20-25), the basic peptides are sometimes referred to as cell penetrating peptides (Column 2, Lines 16-20) and have a range of therapeutic potential including treating cancer (Column 1, Line 63 to Column 2, Line 4). These cell penetrating peptides (CPPs) have been well described in the art as agents to deliver molecules into cells for therapeutic properties, as evidenced by Zhang et al (Pg. 4, 1st Partial Paragraph).
The person of ordinary skill in the art would have been motivated to substitute one known, equivalent element for another to obtain predictable results. The claimed methods would have been obvious because the substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. In the instant case, it would have been obvious to substitute Castillo's cell membrane penetrating peptide KRRK for Lee's cell membrane penetrating peptide RKRK because the cited art teaches equivalency of cell penetrating peptides as useful for molecule delivery to cells.
Therefore, the oncolytic virus as taught by Kim, Lee, Fountzilas, and Massilamany and further in view of Castillo would have been prima facie obvious over the oncolytic virus of the instant application.
Claim 12 remains rejected and claim 20 is newly rejected under 35 U.S.C. 103 as being unpatentable over Kim et al. (Kim DS et al., Gene Ther. 2012) in view of Lee et al. (US9617344 B2, of record) and Fountzilas et al. (Fountzilas C et al., Oncotarget., 2017, of record) and further in view of Massilamany et al. (Massilamany et al., PLOS ONE., 2015, of record) as applied to claim 1 and in further view of Castillo et al (US 10010613 B2, of record) as evidenced by (Zhang P et al., Cell., 2018, of record) as applied to claim 8 and 10 above and in further view of Thermofisher (pVAX1™ User Guide, 2012).
As describe above in the 35 USC 103 rejection, Kim, Lee, Fountzilas, and Massilamany and further in view of Castillo suggest the limitations of claims 1, 8, and 10.
Claims 12 and 20 are directed to the use of the vector pVAX1. pVAX1 was publicly available for cloning of genes and development of vaccines as taught by Thermofisher (entirety of pVAX1™ User Guide). Thermofisher describes that "The vector was constructed to be consistent with Food and Drug Administration (FDA) suggestions regarding plasmid DNA vaccines, and the vector allow high-copy number replication in E.coli and high-level transient expression of the protein of interest in most mammalian cells (Pg. 5). It would have been obvious to a person of ordinary skill at the time of the application to use the pVAX1 vector which has well studied to be an effective vector for use in making a DNA vaccine that would to produce an oncolytic therapeutic as taught by Kim, Lee, Fountzilas, and Massilamany and further in view of Castillo above.
Regarding the rationale for combining prior art elements according to known methods to yield predictable results, all of the claimed elements were known in the prior art and one skilled in the art could have combined the element as claimed by known methods with no change in their respective functions, and the combination would have yielded predictable results to one of ordinary skill in the art at the time of the invention.
Response to Applicants’ Arguments as they apply to the maintained rejections of claims 1, 3-8, 10, 12, 15-16, and newly rejected claims 20-21 under 35 USC§ 103
At pages 10 of the remarks filed on 11/12/2025, applicants provide the following: “To further distinguish from prior art references, Applicant has amended claim 1 to specify that:
• the oncolytic virus is Coxsackievirus B3 (CVB3) strain comprising base mutations ofT97C, Gl180A, Tl654C, Tl756C, G2276A, A2685C, G2690A, C3120A, A3231G, G4327A, T5088C, A5270G, C7026T, and/or G7192A; and
• the exogenous DNA sequence is inserted between 5 'UTR and VP4 of the genome of the oncolytic virus.
These amendments result in claim 1 now reciting the mutations of cancelled claim 11 and provide the new limitation of the insertion site for the DNA sequence. At Pgs. 11-13 of the remarks, applicant summarizes the references used in the 103 rejections of the previous office action filed 8/11/2025 At Pgs. 13-14 applicants essentially argue that “Applicant submits that the cited references Lee, Ma, Fountzilas, Castillo, Zhang, Massilamany, and Thermofisher, alone or in combination, do not teach or suggest the claimed oncolytic virus, in which the oncolytic virus is a CVB3 strain comprising the claimed base mutations, and in which the exogenous DNA sequence is inserted between 5'UTR and VP4 coding region of the CVB3 genome.”
Applicant’s arguments have been considered, but have not been found persuasive.
At Pg. 13 of the remarks, applicant asserts “… although Lee recites a basic peptide, and a vector such as adenovirus, Lee does not teach or suggest an adenovirus vector encoding the basic peptide. Specifically, the basic peptide of Lee, such as RKRK (SEQ ID NO: 18), is a component of the fusion protein. The basic peptide is covalently linked to the targeting moiety, the cleavage site, and the hydrophobic peptide via amide bonds to form the fusion protein. The recombinant vector in Lee encodes the entire fusion protein as a single polypeptide, rather than encoding the basic peptide alone.”
As written, claim 1 does not require that the exogenous DNA is limited to encoding a basic peptide fragment. The claims are "open" and thus lend themselves to additional transgenes, or additional adaptations for the recombinant oncolytic virus. There is no requirement that the only expression adaptation for the recombinant oncolytic virus of instant claim 1 is so limited as argued by Applicant. Therefore, DNA that encodes a basic peptide fragment incorporated into an entire fusion protein as a single polypeptide is relevant prior art.
Applicant asserts that “Lee, however, does not teach or suggest what kind of recombinant virus is useful for the treatment of tumors. A person of ordinary skill in the art, after reviewing Lee, would not have learned what kind of recombinant virus is useful for tumor treatment.”, and that Lee is silent on modification of CVB3 genome.
At the time of the filing of the instant application, the use of CVB3 as an oncolytic virus and the genetic modification of CVB3, including insertion between the 5’UTR and VP4 region, was known. See the modified 103 rejection of claims 1, 3-7, 15-16 above.
Applicant asserts “Although Fountzilas and Massilamany disclose certain oncolytic CVB3 strains, the oncolytic Coxsackie viruses in Fountzilas and Massilamany do not include the claimed mutation sites.” With regard to Applicant’s argument that Lee is silent regarding the construction of a recombinant oncolytic virus based on a CVB3 strain and silent regarding how to insert into the CVB3 genome an exogenous DNA sequence for expressing a basic peptide and increasing the local pH in host cells infected by the recombinant oncolytic virus, the Examiner agrees.
However, Lee is not applied alone, but in combination with Ma, Fountzilas, Castillo, Zhang, Massilamany, and the claimed invention becomes obvious when the references are considered together as a whole rather than each alone.
In this case, Massilamany teaches many of the claimed mutations were known, see table 2 of Massilamany below. At pages 14-15 of the remarks, applicant asserts that it was well known that Coxsackievirus have limited capacity for foreign gene insertion. Applicant remarks that the polynucleotide encoding a fusion protein as taught by Lee is about 552 bp. Applicant further asserts that a skilled artisan would not have been motivated to substitute the adenovirus vector of Lee with a Coxsackie virus because Coxsackie virus are not suitable for stable expression of such a large fusion protein.
Applicants’ statements regarding the “Coxsackie virus are not suitable for stable expression of such a large fusion protein (such as taught by Lee)” are not supported by evidence and are merely attorney arguments. Attorney arguments do not replace evidence where evidence is necessary, see MPEP 2145.
PNG
media_image1.png
655
920
media_image1.png
Greyscale
Moreover, Coxsackie virus can express eGFP which is ~720 bp in length as evidence by Figure 1 of Martínez-Pérez, et al. (Martínez-Pérez, et al.; Viruses, 2025). See attached figure detailing expression of GFP below.
Therefore, applicant’s arguments that Coxsackie viruses are not suitable for the stable expression of such a large fusion protein are not considered persuasive.
Conclusion
No claims are allowed.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KODYE LEE ABBOTT whose telephone number is (703)756-1111. The examiner can normally be reached M-F 8-5.
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, Maria G. Leavitt can be reached on (571) 272-1085. 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.
/KODYE LEE ABBOTT/ Examiner, Art Unit 1634
/MARIA G LEAVITT/ Supervisory Patent Examiner, Art Unit 1634