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 .
Status of Claims
The amended claims filed 01/30/2026 are acknowledged and entered.
Claims 33, 35 and 57 have been amended
Claim 59-62 are cancelled
Claim 63-68 are new
Claims 33-37, 57, 58, and 63-68 are pending and examined on their merits.
Response to Amendment
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office Action.
Claim Rejections - 35 USC § 103 withdrawn
3. The rejections of claims 33-37, 57-62 under 35 U.S.C. 103 as being unpatentable over Crosby (previously cited) in view of NCT04324606 (previously cited) and Ohs (previously cited). are withdrawn in view of Applicant’s amendments to claim 33 and 57 and cancellation of claim 59.
Double Patenting withdrawn
5. The rejections of claims 33-37, 57, 58 on the ground of nonstatutory double patenting as being unpatentable: (1) over claims 1-19 of U.S. Patent US 11,149,286 B1 (16/996,740); (2) over claims 1-19 of U.S. Patent US 12,258,572 B2 (17/469,569); (3) over claims 2 and 4 of copending application 18/368,968 are withdrawn in view of the terminal disclaimers that are being submitted with this reply for US 11,149,286 B1 and US 12,258,572 B2 and the abandonment of 18/368,968.
Rejections Maintained
Claim Rejections - 35 USC § 112 maintained
1. The rejection for claims 33 and 57 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is maintained.
Claims 34-37, 58, and new claims 63-68 are added to this rejection as they depend on either claim 33 or 57, both having been amended.
Applicant’s Arguments: Claims 33 and 57 each recite a single-cycle adenovirus (Sc-Ad) that must comprise a genome lacking at least a portion of a nucleic acid sequence that encodes an adenovirus polypeptide and that must comprise that adenovirus polypeptide. The Examiner asserted that this "is unclear because [[each claim]] refers to a previously mentioned polypeptide no longer found in the genome" Office Action, page 3. Applicant respectfully submits that the adenovirus polypeptide itself is not present in the genome. Further, the recited adenovirus polypeptide does not have to be encoded by the Sc-Ad in order to be present within the Sc-Ad. See Applicant's specification at, for example, page 31, lines 8-25. Accordingly, the claims as previously presented and as presently amended are clear and unambiguous.
Examiner’s Response to Traversal: Applicant’s arguments have been carefully considered but are not found persuasive.
The claims remain indefinite because it is not possible to interpret them in a manner that a person of ordinary skill in the art can practice the invention. The argument that “the recited adenovirus polypeptide does not have to be encoded by the Sc-Ad in order to be present within the Sc-Ad” is also unclear by itself. If the applicant’s intention is to use a Sc-Ad with a gene (partially) deleted along with a transfected cell with a plasmid expressing said gene to rescue the phenotype (page 31, lines 8-25), these are genetic rescue features upon which applicant relies. These features are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).Therefore, these features need to be incorporated as limitations in the claim.
Applicant argues as set forth above. Thus, for the reasons set forth above and the reasons of record, the rejection is maintained.
New Rejections Based on Amendments
Claim Rejections - 35 USC § 103
2. Claims 33-37, 57 and 58 are rejected under 35 U.S.C. 103 as being unpatentable over Crosby (previously cited) in view of NCT04324606 (previously cited) and Tenbusch ( BMC Immunol. 2008 Apr 11;9:13).
Crosby teaches the development of a “single-cycle” Adenovirus (SC-Ad) vector. Such viruses retain their early E1 gene to allow them to replicate their DNA, but the expression of key late gene proteins is deleted, as claimed in independent claims 33 and 57. SC-Ad elicits higher and more persistent transgene-specific antibody (immune) responses than traditional adeno vectors when administered to mammals (Syrian hamsters and rhesus macaques) (page 3, fourth paragraph), also as claimed in claims 33 and 57. Mucosal delivery is taught in page 3, fourth paragraph (After single intranasal needle-free administration (mucosal delivery), mucosal antibody levels climbed over weeks and persisted for more than 6 months.
Crosby teaches that SC-Ad vaccines may hold promise as vaccines against a number of pathogens (in addition to influenza viruses) (page 9, fifth paragraph) (instant claims 33, 35-37).
Crosby does not teach that the SC-Ad vaccine further comprises a genetic adjuvant. In addition, Crosby teaches influenza virus rather than spike polypeptide as recited in instant claims 33 and 57. Crosby further fails to teach humans as the subject to be treated with the vaccine as required in instant claims 34 58, and 60.
NCT04324606 teaches a clinical study in humans with a replication deficient adenovirus vector but using the SARS-CoV-2 spike protein (as the immunogen) (study official title) as required in instant claims 33-37, 57, 58.
NCT04324606 does not teach a nucleic acid encoding a genetic adjuvant.
Tenbusch teaches that Granulocyte-macrophage colony-stimulating factor (GM-CSF) has shown promising results as a cytokine adjuvant for antiviral vaccines (Abstract, background) and there is an application of GM-CSF as an adjuvant for heterologous prime-boost regimens with genetic vaccines, since DNA prime adenoviral vector boost regimens are presently considered as one of the most efficient ways to induce CD8+ T cell in mice, non-human primates and humans responses (that reads on inducing an immune response against a virus and in a mammal), (Abstract, conclusion). Therefore, Tenbusch teaches that a variety of adjuvants including immunomodulatory cytokines such as GM-CSF were explored to improve the efficacy of DNA vaccines, as required in instant claims 33 and 57.
It would have been obvious to one of ordinary skill in the art to combine the teachings of Crosby, NCT04324606 and Tenbusch to develop a method for inducing an immune response in a mammal (human) when administering by mucosal delivery an adenoviral vector expressing an immunogen (SARS-CoV-2 protein) with a genetic adjuvant (an interleukin or other cytokines involved in adaptive immune response stimulation such as GM-CSF). Although the prior art references teach different types of adenoviral vectors (Single-cycle vector due to a pIIIa gene deletion, or replication deficient vector mostly due to an E1 gene deletion), it would be obvious that any type of adenovirus vector would be successful at delivering any gene(s) of interest because gene delivery is the purpose of any viral vector. It would further be obvious that if two genes need to be co-delivered, an immunogen and a genetic adjuvant, they can either be inserted into one or two viral vectors because the rearrangement of parts is considered to be an obvious modification. See MPEP 2144.04(VI)(C). It would further be obvious to exchange the HA gene from influenza virus as taught by Crosby with a SARS-CoV-2 protein as the immunogen as shown by the clinical study NCT04324606 in humans and test different routes of administration as mucosal delivery has been successful in mammals, as taught by Crosby. One of ordinary skill would have been motivated to do so because the use of a viral vector to co-deliver an immunogen and a genetic adjuvant would be a way to induce a strong immune response (as taught by Tenbusch), which would help treating a disorder such as those caused by viral infections. There would be a reasonable expectation of success because tools like viral vectors have been tested in clinical trials and shown to be successful at delivering genes and immunogens (such as the spike protein) and the addition of a genetic adjuvant (such as GM-CSF) have been shown to induce an even stronger immune response when compared to treatment without an adjuvant.
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claims 33, 57 and 63-64 and 66-67 are rejected under 35 U.S.C. 103 as being unpatentable over Crosby (previously cited) in view of NCT04324606 (previously cited), Tenbusch, US10,973,909 (US Patent No. US 10,973,909 B2 Priority date Apr. 7, 2020) and Tort (Virus Research 283 (2020) 19797 Available online 12 April 2020))
The teachings of are discussed above and incorporated herein.
US10,973,909 teaches the sequence of SARS-CoV-2 spike protein (SEQ ID NO; 122) which is 100% identical SEQ ID NO: 1 ( instant claims 63-64 and 66-67)
Title: US-18-017-955-1
Perfect score: 6722
Sequence: 1 MFVFLVLLPLVSSQCVNLTT..........CKFDEDDSEPVLKGVKLHYT 1273
US-16-842-669-122
(NOTE: this sequence has 225 duplicates in the database searched)
Sequence 122, US/16842669
Patent No. 10973909
GENERAL INFORMATION
APPLICANT: TREOS BIO LIMITED
TITLE OF INVENTION: CORONAVIRUS VACCINE
FILE REFERENCE: 52895-708.201
CURRENT APPLICATION NUMBER: US/16/842,669
CURRENT FILING DATE: 2020-04-07
NUMBER OF SEQ ID NOS: 125
SEQ ID NO 122
LENGTH: 1273
TYPE: PRT
ORGANISM: Severe acute respiratory syndrome coronavirus 2
Query Match 100.0%; Score 6722; Length 1273;
Best Local Similarity 100.0%;
Matches 1273; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFS 60
Qy 61 NVTWFHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIV 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 NVTWFHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIV 120
Qy 121 NNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLE 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 NNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLE 180
Qy 181 GKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQT 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 GKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQT 240
Qy 241 LLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDCALDPLSETK 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 LLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDCALDPLSETK 300
Qy 301 CTLKSFTVEKGIYQTSNFRVQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISN 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 CTLKSFTVEKGIYQTSNFRVQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISN 360
Qy 361 CVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIAD 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 CVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIAD 420
Qy 421 YNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPC 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 YNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPC 480
Qy 481 NGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVN 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 481 NGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVN 540
Qy 541 FNFNGLTGTGVLTESNKKFLPFQQFGRDIADTTDAVRDPQTLEILDITPCSFGGVSVITP 600
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 541 FNFNGLTGTGVLTESNKKFLPFQQFGRDIADTTDAVRDPQTLEILDITPCSFGGVSVITP 600
Qy 601 GTNTSNQVAVLYQDVNCTEVPVAIHADQLTPTWRVYSTGSNVFQTRAGCLIGAEHVNNSY 660
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 601 GTNTSNQVAVLYQDVNCTEVPVAIHADQLTPTWRVYSTGSNVFQTRAGCLIGAEHVNNSY 660
Qy 661 ECDIPIGAGICASYQTQTNSPRRARSVASQSIIAYTMSLGAENSVAYSNNSIAIPTNFTI 720
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 661 ECDIPIGAGICASYQTQTNSPRRARSVASQSIIAYTMSLGAENSVAYSNNSIAIPTNFTI 720
Qy 721 SVTTEILPVSMTKTSVDCTMYICGDSTECSNLLLQYGSFCTQLNRALTGIAVEQDKNTQE 780
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 721 SVTTEILPVSMTKTSVDCTMYICGDSTECSNLLLQYGSFCTQLNRALTGIAVEQDKNTQE 780
Qy 781 VFAQVKQIYKTPPIKDFGGFNFSQILPDPSKPSKRSFIEDLLFNKVTLADAGFIKQYGDC 840
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 781 VFAQVKQIYKTPPIKDFGGFNFSQILPDPSKPSKRSFIEDLLFNKVTLADAGFIKQYGDC 840
Qy 841 LGDIAARDLICAQKFNGLTVLPPLLTDEMIAQYTSALLAGTITSGWTFGAGAALQIPFAM 900
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 841 LGDIAARDLICAQKFNGLTVLPPLLTDEMIAQYTSALLAGTITSGWTFGAGAALQIPFAM 900
Qy 901 QMAYRFNGIGVTQNVLYENQKLIANQFNSAIGKIQDSLSSTASALGKLQDVVNQNAQALN 960
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 901 QMAYRFNGIGVTQNVLYENQKLIANQFNSAIGKIQDSLSSTASALGKLQDVVNQNAQALN 960
Qy 961 TLVKQLSSNFGAISSVLNDILSRLDKVEAEVQIDRLITGRLQSLQTYVTQQLIRAAEIRA 1020
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 961 TLVKQLSSNFGAISSVLNDILSRLDKVEAEVQIDRLITGRLQSLQTYVTQQLIRAAEIRA 1020
Qy 1021 SANLAATKMSECVLGQSKRVDFCGKGYHLMSFPQSAPHGVVFLHVTYVPAQEKNFTTAPA 1080
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1021 SANLAATKMSECVLGQSKRVDFCGKGYHLMSFPQSAPHGVVFLHVTYVPAQEKNFTTAPA 1080
Qy 1081 ICHDGKAHFPREGVFVSNGTHWFVTQRNFYEPQIITTDNTFVSGNCDVVIGIVNNTVYDP 1140
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1081 ICHDGKAHFPREGVFVSNGTHWFVTQRNFYEPQIITTDNTFVSGNCDVVIGIVNNTVYDP 1140
Qy 1141 LQPELDSFKEELDKYFKNHTSPDVDLGDISGINASVVNIQKEIDRLNEVAKNLNESLIDL 1200
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1141 LQPELDSFKEELDKYFKNHTSPDVDLGDISGINASVVNIQKEIDRLNEVAKNLNESLIDL 1200
Qy 1201 QELGKYEQYIKWPWYIWLGFIAGLIAIVMVTIMLCCMTSCCSCLKGCCSCGSCCKFDEDD 1260
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1201 QELGKYEQYIKWPWYIWLGFIAGLIAIVMVTIMLCCMTSCCSCLKGCCSCGSCCKFDEDD 1260
Qy 1261 SEPVLKGVKLHYT 1273
|||||||||||||
Db 1261 SEPVLKGVKLHYT 1273
Tort teaches a comprehensive analysis of the genome composition and codon usage
patterns of emerging coronaviruses (title and entire article). A codon usage, amino acid usage,
dinucleotide frequencies, base composition, the relative synonymous codon usage (RSCU),
total GC content, GC content in the third position of the codon (GC3s) and effective numbers of
codons (ENC) were calculated using the program CodonW ((page 2, second column, 2nd
paragraph). Table 1, 2 and section 3.5 teach the codon usage adaptation in SARS-CoV-2 (which would include the spike protein as it is looking at the entire genome), (instant claims 64 and 67) ).
It would have been obvious to one of ordinary skill in the art to combine the teachings of Crosby, NCT04324606 and Tenbusch to develop a method for inducing an immune response in a mammal (human) when administering an adenoviral vector expressing an immunogen (the SARS-CoV-2 spike protein taught by US10,973,909, with a genetic adjuvant (such as GM-CSF). Although the prior art references teach different types of adenoviral vectors, it would have been obvious that any type of adenovirus vector would be successful at delivering any gene(s) of interest because gene delivery is the purpose of any viral vector. It would have further been obvious to codon optimize the nucleotide sequence encoding the SARS-CoV-2 spike protein as taught by Tort. One of ordinary skill would have been motivated to do so because the use of a viral vector to co-deliver any immunogen and any genetic adjuvant would be a way to induce a strong immune response (as taught by Tenbusch) and codon optimization of a nucleic acid helps increase protein expression. A strong immune response would help treating a disorder such as those caused by viral infections. There would be a reasonable expectation of success because tools like viral vectors have been tested in clinical trials and shown to be successful at delivering codon optimized genes and immunogens (such as the spike protein, which is known to be immunogenic) and the addition of a genetic adjuvant (such as GM-CSF) have been shown to induce an even stronger immune response when compared to treatment without an adjuvant.
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Relevant arguments that apply to new claims
Applicant’s Arguments: At no point does the combination of cited references teach or suggest that a person having ordinary skill in the art should make or use the presently claimed SC-Ad. To further prosecution, however, claims 33 and 57 were amended herein to recite that the SC-Ad includes (a) a nucleic acid sequence encoding a Spike polypeptide and (b) a nucleic acid sequence encoding an adjuvant polypeptide selected from the group consisting of a GM-CSF polypeptide, a Clostridium difficile TcdA polypeptide, a C. difficile TcdB polypeptide, and a C. difficile polypeptide TcdA/B fusion polypeptide.
The Crosby reference discloses intranasal administration of SC-Ad vectors that express the influenza A/PR/8/34 hemagglutinin gene. NCT04324606 discloses intramuscular administration of ChAdOx1 vectors that express a Spike polypeptide. The Ohs reference discloses adenoviral vectors that encode an interleukin as a genetic adjuvant. However, the combination of these references fails to teach or suggest that a person having ordinary skill in the art should make or use a SC-Ad that include (a) a nucleic acid sequence encoding a Spike polypeptide and (b) a nucleic acid sequence encoding an adjuvant polypeptide selected from the group consisting of a GM-CSF polypeptide, a Clostridium difficile TcdA polypeptide, a C. difficile TcdB polypeptide, and a C. difficile polypeptide TcdA/B fusion polypeptide as presently claimed. Thus, the presently pending claims are patentable over the combination of cited references.
Examiner’s Response to Traversal: The new Claim Rejections - 35 USC § 103
where claims 33-37, 57 and 58 are rejected under 35 U.S.C. 103 as being unpatentable over Crosby in view of NCT04324606 and Tenbusch address the amended limitations of the independent claims and the change from interleukins to CM-CSF. Claims 63-64 and 66-67 are rejected under 35 U.S.C. 103 as being unpatentable over Crosby in view of NCT04324606, Tenbusch, US10,973,909 and Tort address the limitations of the new claims.
In addition, applicant is reminded that 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). Applicant has not sufficiently described why there is no prima facie case for obviousness.
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.
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/IMMA BARRERA/
Examiner, Art Unit 1671
/Michael Allen/Supervisory Patent Examiner, Art Unit 1671