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 Arguments
The Amendment filed 04/27/2026 in which claims 30 – 41 and 43 – 46 were amended has been entered. Claims 1 – 29 were previously cancelled. Claim 42 has been cancelled in the amended claims.
Claims 30 – 41 and 43 – 46 are under examination on the merits.
Claim Objections
(Previous objection, withdrawn as to claims 30 – 46)
Applicant has cancelled claim 42.
Applicant’s amendment to claims 30 – 41 and 43 – 46 have overcome previous objections to that claim.
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.
(Previous rejection, withdrawn as to claim 35) Applicant’s amendment to claim 35 has overcome previous rejections to that claim.
Claim Rejections - 35 USC § 112
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.
(Previous rejection, withdrawn as to claim 31) Applicant’s amendment to claim 31 has overcome previous rejections to that claim.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
(Previous rejection, maintained and modified as to claims 30, 32, 34, 36, 37, 41, and 43 – 45 in view of the amendment, withdrawn as to claim 42)
Applicant has cancelled claim 42.
Claims 30, 32, 34, 36, 37, 41, and 43 – 45 are rejected under 35 U.S.C. 103 as being unpatentable over Jia et al. (US 20190169253 A1, hereinafter, "Jia"), and in further view of Champion et al. (US 10124028 B2, hereinafter, “Champion”).
With regard to Claims 30, 34, and 37, Jia teaches an oncolytic herpes simplex viral vector comprising an expression cassette of one or more of IL-12, IL-15, and IL-15Ra (Abstract), with the IL-15Ra being limited to the sushi domain of IL-15Ra (¶ 0023, Figure 9A, reproduced below). As evidenced by Wei et al. (J Immunology, 2001), the sushi domain of IL-15Ra lacks a transmembrane component (Figure 1).
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Regarding claim 32, Jai teaches the sushi domain in the G4 position (Figure 13A, reproduced below.)
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Regarding claim 36, Jia teaches the IL-12 in the G2 position (Figure 5, reproduced below.)
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Regarding claim 41, Jia teaches the expression cassette can be one or more of IL-12, IL-15, and IL-15Ra (Abstract), which includes having only IL-12 and IL-15 resulting in m being 0.
Regarding claim 43, SEQ ID NO: 177 encodes for a polypeptide comprised of IL-12, IL-15Ra, and IL-15. Amino acids 1 - 549 correspond to IL-12, 550 – 567 correspond to a 2A peptide, and 568 – 810 correspond to IL-15Ra. Jia teaches an expression cassette of one or more of IL-12, IL-15, and IL-15Ra (Abstract). The overall structure and function of the protein is taught by Jia as an expression cassette of IL-12 and IL-15Ra is recited in the abstract. In this case, Figure 5 of Jia shows at least an IL-12 sequence followed by a 2A peptide that is upstream of IL-15Ra.
Furthermore, Wong et al. (US20200071374A1) teaches multi chain fusion polypeptide comprising of IL-12 fused to IL-15Ra sushi domain (Sequence 122, Page 142, ¶757). Notably, the IL-12 sequence, identified is “Query” has a 95.9% match with the IL-12 sequence of Wong, identified is “Sbjct” (reproduced below).
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The reference fails to teach the use of an adenovirus backbone, using a major late promoter to regulate transgene expression, a pharmaceutical carrier for the vector, or using the adenovirus to treat cancer.
However, Champion teaches using an oncolytic virus adenovirus that encodes either an insoluble or soluble variant of IL-15 (Col. 21, Line 36 - 40). With regards to the adenovirus backbone, the applicant has described the common backbone of an adenovirus (Figure 1), including a restriction site found at BX in Human Adenovirus 3 (Figure 2). As such, Singh et al. (Adenoviruses, 2018, hereinafter, Singh) describe an adenovirus comprising of E1A-E1B, followed by E2B-L1-L2-L3-L4, which is connected to E3, which in turn is connected to L5.
[AltContent: textbox ([img-media_image5.png]
Figure 1. Adenovirus structure. Singh (Adenoviruses, 2018))][AltContent: textbox ([img-media_image6.png]
Figure 2. mscI restriction site located at the beginning of L5. Lin et al. (Genome Res, 2006))]
Regarding claim 30, Champion teaches an oncolytic adenovirus with a major late promoter regulating transgene expression (Col 23, Line 58 - 65).
Regarding claim 44, Champion teaches pharmaceutical carriers of the oncolytic virus can be formulated with HEPES buffer (Col 40, Line 5 – 18).
Regarding claim 45, Champion teaches administering a therapeutically effective amount of adenovirus to treat cancer (Col. 42, Line 4 – 12).
Jia and Champion are both considered to be analogous to the claim invention because they are in the same field of treating cancer through oncolytic viruses. Therefore, it would have been prima facie obvious before the effective filing date of the claimed invention to utilize the art-recognized method to encode IL-15/IL-15Ra sushi domain chimeric protein, as demonstrated by Jia, within an adenovirus, as taught by Champion, because doing so would advantageously increase viral spread and activity, thereby increasing probability of affecting cancerous cells. One of ordinary skill in the art would have reasonable expectation of success in using different viral vector backbones to increase efficacy of cancer treatment given that this method is well known, has been successfully demonstrated, and commonly used in the prior art.
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill in the art at the time of filing especially in the absence of evidence to the contrary.
(Previous rejection, maintained and modified as to claims 33, 38, 39, 40, and 46 in view of the amendment)
Claims 33, 38, 39, 40, and 46 are rejected under 35 U.S.C. 103 as being unpatentable over Jia and Champion as applied to claims 30, 32, 34, 36, 37, 41, and 43 – 45 above, and further in view of Ma et al. (US20210338729A1, hereinafter, "Ma").
As discussed above, claims 30, 32, 34, 36, 37, 41, and 43 – 45 were rendered prima facie obvious by the teachings of Jia and Champion. The references fail to teach encoding IL-2 leader sequence, at least one chemokine such as CCL-19 within an adenovirus backbone or the use of a virus in combination with cellular therapy.
However, regarding claim 33, Ma teaches that a polynucleotide for a chimeric antigen receptor (CAR) molecule can be comprised of an IL-2 leader sequence followed by IL-15/IL-15Ra sushi domain complex (¶272, 325), which can be cloned into an adenovirus vector (¶275).
Regarding claim 38, Ma teaches that the polynucleotide can be comprised of a chemokine (¶210).
Regarding claim 39, Ma teaches that the polynucleotide can be comprised of CCL-19 (¶210).
Regarding claim 40, Ma teaches the CCL-19 can be encoded in G3. (¶210).
Regarding claim 46, Ma teaches the use of viral vectors for cellular therapy (¶282 – 287).
Ma, Jia, and Champion are considered to be analogous to the claim invention because they are in the same field of treating cancer through oncolytic viruses. Therefore, it would have been prima facie obvious before the effective filing date of the claimed invention to utilize the art-recognized method to include an IL-2 leader sequence with a IL-15/IL-15Ra sushi domain, IL-12, and CCL-19, with positioning of CCL-19 downstream of the cytokines, and use the viral vector in combination with cellular therapy, as taught by Ma, with the method as taught by Jia and Champion, because doing so would advantageously increase viral spread and payload secretion efficiency, thereby increasing probability of affecting cancerous cells. One of ordinary skill in the art would have reasonable expectation of success in using different protein components for a chimeric antigen receptor protein to increase efficacy of cancer treatment given that this method is well known, has been successfully demonstrated, and commonly used in the prior art.
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill in the art at the time of filing especially in the absence of evidence to the contrary.
(Previous rejection, maintained and modified as to claim 35 in view of the amendment)
Claim 35 is rejected under 35 U.S.C. 103 as being unpatentable over Jia and Champion as applied to claims 30, 32, 34, 36, 37, 41, and 43 – 45 above, and further in view of Lieschke et al. (Nature Biotechnology, 1997, hereinafter, “Lieschke”).
As discussed above, claims 30, 32, 34, 36, 37, 41, and 43 – 45 were rendered prima facie obvious by the teachings of Jia and Champion. The references fail to teach encoding IL-12 sequence, described as a “single chain fusion protein… in the format p40-linker-p45… wherein the linker comprises one or more units of Gly4Ser” and as “mature human IL-12 p70 single chain protein with a (Gly4Ser)3 linker joining the IL12p40”.
However, regarding claim 35, Lieschke teaches the use of IL-12 fusion protein, known as IL-12.p40L▲p35, which is “comprised of the p40 subunit linked by a (Gly4Ser)3 linker to the p35 subunit” (Introduction: ¶2) that retain potent antitumor activity. Amino acids 1 – 306 of SEQ ID NO: 115 share a sequence similarity with IL-12.p40, 307 to 321 is a (Gly4Ser)3 linker and amino acids 322 – 517 share a sequence similarity with IL-12.p37. Together, SEQ ID NO: 115 shares the function and protein design as taught by Lieschke. Furthermore, this protein sequence is found in prior art such as in Winston et al. (US20190367576A1, hereinafter, “Winston”). SEQ ID NO: 115, identified is “Qy” has a 100% match with Winston, identified as “Db” (reproduced below), further
RESULT 3
US-16-438-166-45
(NOTE: this sequence has 14 duplicates in the database searched)
Sequence 45, US/16438166
Publication No. US20190367576A1
GENERAL INFORMATION
APPLICANT: WEREWOLF THERAPEUTICS, INC.
TITLE OF INVENTION: ACTIVATABLE INTERLEUKIN 12 POLYPEPTIDES AND METHODS OF USE
TITLE OF INVENTION: THEREOF
FILE REFERENCE: 105365-0027
CURRENT APPLICATION NUMBER: US/16/438,166
CURRENT FILING DATE: 2019-06-11
PRIOR APPLICATION NUMBER: PCT/US2019/032322
PRIOR FILING DATE: 2019-05-14
PRIOR APPLICATION NUMBER: 62/756,507
PRIOR FILING DATE: 2018-11-06
PRIOR APPLICATION NUMBER: 62/756,515
PRIOR FILING DATE: 2018-11-06
PRIOR APPLICATION NUMBER: 62/756,504
PRIOR FILING DATE: 2018-11-06
PRIOR APPLICATION NUMBER: 62/671,225
PRIOR FILING DATE: 2018-05-14
NUMBER OF SEQ ID NOS: 92
SEQ ID NO 45
LENGTH: 524
TYPE: PRT
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
polypeptide
Query Match 100.0%; Score 2741; Length 524;
Best Local Similarity 100.0%;
Matches 518; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 IWELKKDVYVVELDWYPDAPGEMVVLTCDTPEEDGITWTLDQSSEVLGSGKTLTIQVKEF 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 IWELKKDVYVVELDWYPDAPGEMVVLTCDTPEEDGITWTLDQSSEVLGSGKTLTIQVKEF 60
Qy 61 GDAGQYTCHKGGEVLSHSLLLLHKKEDGIWSTDILKDQKEPKNKTFLRCEAKNYSGRFTC 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 GDAGQYTCHKGGEVLSHSLLLLHKKEDGIWSTDILKDQKEPKNKTFLRCEAKNYSGRFTC 120
Qy 121 WWLTTISTDLTFSVKSSRGSSDPQGVTCGAATLSAERVRGDNKEYEYSVECQEDSACPAA 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 WWLTTISTDLTFSVKSSRGSSDPQGVTCGAATLSAERVRGDNKEYEYSVECQEDSACPAA 180
Qy 181 EESLPIEVMVDAVHKLKYENYTSSFFIRDIIKPDPPKNLQLKPLKNSRQVEVSWEYPDTW 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 EESLPIEVMVDAVHKLKYENYTSSFFIRDIIKPDPPKNLQLKPLKNSRQVEVSWEYPDTW 240
Qy 241 STPHSYFSLTFCVQVQGKSKREKKDRVFTDKTSATVICRKNASISVRAQDRYYSSSWSEW 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 STPHSYFSLTFCVQVQGKSKREKKDRVFTDKTSATVICRKNASISVRAQDRYYSSSWSEW 300
Qy 301 ASVPCSGGGGSGGGGSGGGGSRNLPVATPDPGMFPCLHHSQNLLRAVSNMLQKARQTLEF 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 ASVPCSGGGGSGGGGSGGGGSRNLPVATPDPGMFPCLHHSQNLLRAVSNMLQKARQTLEF 360
Qy 361 YPCTSEEIDHEDITKDKTSTVEACLPLELTKNESCLNSRETSFITNGSCLASRKTSFMMA 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 YPCTSEEIDHEDITKDKTSTVEACLPLELTKNESCLNSRETSFITNGSCLASRKTSFMMA 420
Qy 421 LCLSSIYEDLKMYQVEFKTMNAKLLMDPKRQIFLDQNMLAVIDELMQALNFNSETVPQKS 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 LCLSSIYEDLKMYQVEFKTMNAKLLMDPKRQIFLDQNMLAVIDELMQALNFNSETVPQKS 480
Qy 481 SLEEPDFYKTKIKLCILLHAFRIRAVTIDRVMSYLNAS 518
||||||||||||||||||||||||||||||||||||||
Db 481 SLEEPDFYKTKIKLCILLHAFRIRAVTIDRVMSYLNAS 518
Lieschke, Jia, and Champion are considered to be analogous to the claim invention because they are in the same field of treating cancer through by leveraging interleukin. Therefore, it would have been prima facie obvious before the effective filing date of the claimed invention to utilize the art-recognized method to include the proven effective IL-12.p40L▲p35 as taught by Lieschke, with the method as taught by Jia and Champion, because doing so would advantageously increase antitumor activity, thereby increasing probability of affecting cancerous cells. One of ordinary skill in the art would have reasonable expectation of success in using the fusion protein to increase efficacy of cancer treatment given that this method is well known, has been successfully demonstrated, and commonly used in the prior art.
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill in the art at the time of filing especially in the absence of evidence to the contrary.
Response to Arguments
Applicant's arguments filed 04/27/2026 have been fully considered but they are not persuasive.
Applicant contends on page 5 of the Remarks: 35 U.S.C. § 112 rejection: claims 31 and 35 have been amended to overcome the rejection
In response: The 35 U.S.C. § 112 rejection to claims 31 and 35 has been withdrawn.
Applicant contends on page 6 of the Remarks: 35 U.S.C. § 103 rejection: Applicant states the adenovirus is optimized to improve expression of IL-15 from a group B adenovirus when at least one further transgene is present. Applicant state that the IL-15 must be the last in a sequence of at least two transgenes. Furthermore, IL-15 can be expressed alone or with a sushi domain, where the first transgene is the sushi domain and the second is IL-15.
Applicant states that Jia does not teach this particular arrangement.
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In response: The 35 U.S.C. § 103 rejection is maintained. As discussed previously and above, Jia clearly teaches IL-15 in the last position of an expression cassette along with a sushi domain in the first position (Figure 9a, reproduced below). Both of these transgenes are driven by a bidirectional promoter. This expression cassette alone teaches the IL-15 transgene in the last position.
Jia also teaches an expression cassette where IL-12 is followed by IL-15 linked to a sushi domain (Figure 17a, reproduced below). This expression cassette shows that the IL-15 can be last in the sequence of transgene and can be linked to the sushi domain.
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As such the teachings of Jia in view of Champion teach the limitations of claims 30, 32, 34, 36, 37, 41, and 43 – 45.
Applicant contends on page 9 of the Remarks: Applicant states that Ma and Lieschke do not provide teachings to cure the deficiencies of Jia and Champion
In response: Applicant’s arguments have been full considered but they are not persuasive. As discussed above, Applicant’s arguments were not persuasive for claims 30, 32, 34, 36, 37, 41, and 43 – 45 and, as such, the previous rejection is maintained and modified in view of amendments for all dependent claims.
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 Danyal H Alam whose telephone number is (571)272-1102. The examiner can normally be reached M - F 9am - 5pm.
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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.
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/DANYAL HASSAN ALAM/Examiner, Art Unit 1672
/THOMAS J. VISONE/Supervisory Patent Examiner, Art Unit 1672
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