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 .
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission of RCE on 9/5/25 and the amendment of claims has been entered.
Election/Restrictions
Applicant's election with traverse of Group I in the reply filed on 12/9/22 was previously acknowledged. Applicants elected ferritin and TRAIL.
The requirement was deemed proper and made FINAL.
In the reply filed 6/6/24, Applicants amended claims 1, 4 and 6-8 were amended. Claims 2-3 were canceled. Claims 24-25 are newly added.
In the reply filed 1/8/25, Applicants did not amend any claims.
In the RCE filed 9/5/25, Applicants amended claims 1, 4, 8, 24-25 and added NEW claims 26-38.
Claims 1 and 4-38 are pending.
Claims 11-23 and 26-38 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected group, there being no allowable generic or linking claim.
Claims 1, 4-10 and 24-25 read on the elected Group I and species and are under consideration.
Claim Objections-Withdrawn
The objection to claim 25 under 37 CFR 1.75 as being a substantial duplicate of claim 6 is withdrawn due to amendment of claim 25.
Claim Rejections-Withdrawn
The rejection of claims 1, 4-5. 7-9 and 24 under 35 U.S.C. 103 as being unpatentable over Stuckey et al. (“TRAIL on TRIAL: preclinical advanced for cancer therapy” Tren Mol Med. 2013 November; 19(11)) in view of Ceci et al. (WO 2016/051340) is withdrawn due to amendment of the claims.
The rejection of claims 1, 4-9 and 24-25 under 35 U.S.C. 103 as being unpatentable over Stuckey et al. (“TRAIL on TRIAL: preclinical advanced for cancer therapy” Tren Mol Med. 2013 November; 19(11)) and Ceci et al. (WO 2016/051340) in view of Uniprot P50591 TNF10-Human (https://www.uniprot.org/uniprotkb/P50591/entry>Oct 1996, previously presented) is withdrawn due to amendment of the claims.
The rejection of claims 1, 4-5, 7-10 and 24 under 35 U.S.C. 103 as being unpatentable over Stuckey et al. (“TRAIL on TRIAL: preclinical advanced for cancer therapy” Tren Mol Med. 2013 November; 19(11)) and Ceci et al. (WO 2016/051340) in view of Chen et al. (“Fusion Protein Linkers: Property, Design and Functionality” Adv Drug Deliv rev 2013; 65 (10) is withdrawn due to amendment of the claims.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, 5, 7 and 8 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (“Immunoglobulin Fc Domain Fusion to TRAIL Significantly Prolongs its plasma half-life and enhances its antitumor activity” Mol Cancer ther (2014) 13(3):643-650) in view of Liang et al. (PNAS 2014 oct 14; 111(41): 14900-5) and Morris et al. (mBio. 2017 Feb 28;8(1)).
Wang et al. teach TRAIL is a potent induce of cells death and can kill a wide variety of human cancer cells without killing normal cells (Abstract). Wang et al. teach that TRAIL has a very short plasma half-life which limits its therapeutic potential (Abstract). Wang et al. teach fusion of TRAIL to Fc to enhance its stability. Wang et al. teach fusion to Fc improved bioavailability and activity of TRAIL (Abstract and Fig. 4).
Wang et al. does not teach fusion of TRAIL to a ferritin heavy chain or light chain. However, the teachings of Liang et al. and Morris et al. cure this deficiency.
Liang et al. teach that ferritin heavy chain forms self-assembling nanocage structure that can be used as a delivery scaffold for anticancer agents, providing enhanced tumor targeting and accumulation, thereby improving therapeutic efficacy (Abstract and Intro). Liang et al. teach that natural ferritin nanocarriers are expected to possess an outstanding biocompatibility and safety profile because they exist naturally in the human body and are composed of nontoxic elements that therefore would not activate inflammatory or immunological responses (p. 14900, bottom of 1st col. to top of 2nd col.). Liang et al. teach ferritin nanocages comprising Dox (anticancer agent) exhibited more than 10-fold higher intratumoral drug concentration compared to free Dox and significantly inhibited tumor growth after a single dose injection (Abstract).
Morris et al. teach that ferritin nanoparticles and Fc regions are both multivalent carrier scaffolds to display fusion proteins (Abstract).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the invention to substitute the Fc region of Wang et al. with the ferritin heavy chain. MPEP 2143 states: Exemplary rationales that may support a conclusion of obviousness include the rationale that simple substitution of one known element for another to obtain predictable results. To reject a claim based on this rationale, Office personnel must resolve the Graham factual inquiries. Then, Office personnel must articulate the following:
(1) a finding that the prior art contained a device (method, product, etc.) which differed from the claimed device by the substitution of some components (step, element, etc.) with other components;
(2) a finding that the substituted components and their functions were known in the art;
(3) a finding that one of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have been predictable; and
(4) whatever additional findings based on the Graham factual inquiries may be necessary, in view of the facts of the case under consideration, to explain a conclusion of obviousness.
The prior art teaches TRAIL fused to Fc. Ferritin was recognized as an alternative multivalent scaffold capable of improving delivery and functional display of therapeutic proteins. Morris et al. teach that both Fc and Ferritin were know to perform the same function of multivalent scaffolds for proteins. There is a reasonable expectation of success given that both Fc and ferritin are established multivalent scaffolds and Liang et al. teach that ferritin heavy chain self assembles into stable nanocage capable of delivering functional payloads.
With respect to limitation of “consisting of a TNF superfamily protein linked to a ferritin heavy chain” (Claim 1) and “a fusion protein consisting of a TNF superfamily protein linked to a ferritin heavy chain …via a linker peptide…” (Claim 8), it would have been obvious to a person of ordinary skill in the art to include or omit a linker as a matter of routine protein engineering design choice. It is well established that linkers may be optionally employed in fusion protein to provide flexibility or improve folding while in other instances fusion proteins are designed to be directly joined. Therefore, one of ordinary skill in the art would have the choice to use a linker or not as both choices are routine in the art. There is a reasonable expectation of success given that both choices would have been expected to produce a functional fusion protein.
With respect to claim 5, Wang et al. teach TRAIL.
With respect to claim 7, Wang et al. teach Fc fused to the N-terminus of TRAIL. It would have been obvious to a person of ordinary skill in the art to optimize fusion at the N or C-terminus with a reasonable expectation of success.
Claims 1, 4-5, 7 and 8 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (“Immunoglobulin Fc Domain Fusion to TRAIL Significantly Prolongs its plasma half-life and enhances its antitumor activity” Mol Cancer ther (2014) 13(3):643-650), Liang et al. (PNAS 2014 oct 14; 111(41): 14900-5) and Morris et al. (mBio. 2017 Feb 28;8(1)) in view of Uniprot (P0274-FRIH_Human, integrated into UniprotKB 1986).
The references do not teach the amino acid sequence of ferritin is SEQ ID NO: 6. However, the teachings of Uniprot cures this deficiency.
Uniprot teaches the sequence of the human ferritin heavy chain that is identical to instantly claimed SEQ ID NO: 6.
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With respect to claim 4, It would have been obvious to use the heavy chain ferritin sequence of Uniprot because Uniprot teaches the sequence is human ferritin heavy chain. There is a reasonable expectation of success given that the sequence of human heavy chain ferritin is known in the art and provided in the Uniprot database.
Claims 1, 5-8 and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (“Immunoglobulin Fc Domain Fusion to TRAIL Significantly Prolongs its plasma half-life and enhances its antitumor activity” Mol Cancer ther (2014) 13(3):643-650), Liang et al. (PNAS 2014 oct 14; 111(41): 14900-5) and Morris et al. (mBio. 2017 Feb 28;8(1)) in view of Uniprot P50591 TNF10-Human (https://www.uniprot.org/uniprotkb/P50591/entry>Oct 1996, previously presented).
With respect to claims 6 and 25, Uniprot teaches the amino acid sequence of human TRAIL, that is 99.5% identical to instantly claimed SEQ ID NO: 2. MPEP 2144.05 states obviousness of similar and overlapping ranges, amounts and proportions. In particular, MPEP 2144.05 states: a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v.Banner, 778 F.2d 775, 783,227 USPQ 773, 779 (Fed. Cir. 1985) (Court held as proper a rejection of a claim directed to an alloy of “having 0.8% nickel, 0.3% molybdenum, up to 0.1% iron, balance titanium” as obvious over a reference disclosing alloys of 0.75% nickel, 0.25% molybdenum, balance titanium and 0.94% nickel, 0.31% molybdenum, balance titanium. “The proportions are so close that prima facie one skilled in the art would have expected them to have the same properties.”). In the instant case, the UniProt teaches the sequence of human TRAIL, which is 99.5% identical to the claimed SEQ ID NO: 2 . There is a reasonable expectation of success given the great similarity between sequences having 99.5% identity to SEQ ID NO: 2, one of ordinary skill in the art would reasonably conclude that the sequences have similar properties.
. Claims 1, 5, 7-10 and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (“Immunoglobulin Fc Domain Fusion to TRAIL Significantly Prolongs its plasma half-life and enhances its antitumor activity” Mol Cancer ther (2014) 13(3):643-650), Liang et al. (PNAS 2014 oct 14; 111(41): 14900-5) and Morris et al. (mBio. 2017 Feb 28;8(1)) in view of Chen et al. (“Fusion Protein Linkers: Property, Design and Functionality” Adv Drug Deliv rev 2013; 65 (10).
The references do not teach the linkers, however the teachings of Chen et al. cure this deficiency.
Chen et al. teach that linkers have shown increasing importance in the construction of stable bioactive fusion proteins (Abstract). Chen et al. teach examples of linkers including A(EAAAK)4ALEA(EAAAK)4 that meets the limitations of SEQ ID NO: 4 for increased expression (Table 3). Table 3 also discloses G8, meeting the limitation of SEQ ID NO: 21 for increases stability and folding. Table 3 also discloses G4S, meeting the limitation of SEQ ID NO: 31 for improved biological activity.
It would have been obvious to one of ordinary skill in the art to optimize the linker of the fusion protein made obvious by Wang et al., Liang et al. and Morris et al. in order to create a stable fusion protein. A person would look to the teachings of Chen et al. and decide to choose SEQ ID NO: 4 if increased expression is needed, SEQ ID NO: 21 if increased stability is needed or SEQ ID NO: 31 if improved biological activity is needed. There is a reasonable expectation of success given that linkers are common in the art and the fusion protein of Ceci et al. contains a linker sequence.
Response to Arguments
Applicant's arguments filed 9/5/25 have been fully considered but they are not persuasive. Applicant’s arguments with respect to the Ceci reference have been considered but are moot because the new ground of rejection does not rely on the reference. Applicants argue that PHOSITA would not have a reasonable expectation of conjugating TRAIL to ferritin heavy chain because investigations into the pharmacokinetics of TRAIL and ferritin heavy chains have revealed that both have short half lives (refs submitted in IDS filed 9/5/25). Applicants argue advantageous properties of the claimed fusion proteins are not solely due to half-life extension. Applicants argue that the trimer structure is important for stability and biological function. Applicants argue that it is the present invention that teaches fusion proteins as claimed demonstrate that they allow TNF super family members to form active homotrimers on the surface of the 24-octahedral cage structure formed by the ferritin heavy chain.
This argument is not persuasive at because Wang teaches that TRAIL can be fused to another protein and retain its biological activity. Importantly, its known in the art and taught by Morris and Liang that Fc and ferritin heavy chain are know multivalent scaffolds for presentation of proteins. Liang teaches that ferritin forms self-assembling nanocages. Therefore, the combined references would provide a reasonable expectation that TRAIL could be fused to ferritin and presented in a functional multivalent form. Importantly, the same fusion protein would have the same properties.
Furthermore, the Applicants present data related specifically to a fusion protein comprising TRAIL and HFt. However, the claims are more broadly drawn to fusion proteins comprising any TNF superfamily member and either a ferritin heavy chain or light chain. The data does not establish that the asserted advantages or properties extend across the full scope of the claimed invention. The data is therefore not commensurate in scope with the claims (see MPEP 2145).
Double Patenting-Maintained
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
The rejection of claims 1, 4-10 and 24-25 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 of USPN 12,577,292 (previously copending Application No. 17/436,070) is maintained. Please note this rejection has been modified due to allowance of the copending application.
Although the claims at issue are not identical, they are not patentably distinct from each other because the copending Application claims a fusion polypeptide comprising human TRAIL (SEQ ID NO: 1) a linker and human ferritin heavy chain (SEQ ID NO: 2). The fusion polypeptide of the copending Application also includes a linker sequence. With respect to limitation of “consisting of a TNF superfamily protein linked to a ferritin heavy chain” (Claim 1) and “a fusion protein consisting of a TNF superfamily protein linked to a ferritin heavy chain …via a linker peptide…” (Claim 8), it would have been obvious to a person of ordinary skill in the art to include or omit a linker as a matter of routine protein engineering design choice. It is well established that linkers may be optionally employed in fusion protein to provide flexibility or improve folding while in other instances fusion proteins are designed to be directly joined. Therefore, one of ordinary skill in the art would have the choice to use a linker or not as both choices are routine in the art. There is a reasonable expectation of success given that both choices would have been expected to produce a functional fusion protein.
Response to Arguments
Applicant's arguments filed 6/6/24 have been fully considered but they are not persuasive. Applicants argue that the instant Application is earlier filed than the copending application and thus in accordance with MPEP 1490 should be withdrawn.
This argument is not persuasive because the copending application was patented.
Conclusion
No claims are allowed.
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/TARA L MARTINEZ/Examiner, Art Unit 1654