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 .
DETAILED ACTION
Status of Application, Amendments, and/or Claims
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 filed on 12/04/2025 has been entered.
Claims 1, 8, 15, and 18-19 are pending and currently under consideration.
It is noted that the section (ii) on page 3 of the office action mailed on 08/06/2025 should be replaced by the following paragraph:
(ii). Claims 1, 8, 15-16, and 18-19 are rejected under 35 U.S.C. 112(a), as failing to comply with the written description requirement. The claim(s) contains subject matter, which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor at the time the application was filed, had possession of the claimed invention. The basis for the rejection is set forth in the office action mailed on 04/25/2025.
Withdrawn Objections and/or Rejections
The rejection of claims 1, 8, 15-16, and 18-19 under 35 U.S.C. 112(b) is withdrawn in view of amended claim 1.
The rejection of claims 1, 8, 15-16, and 18-19 under 35 U.S.C. 103(a) as being unpatentable over WO 2008/124086 A2 (October 16, 2008) in view of Loetscher et al. (J. Biol. Chem. 268 (35): 26350-26357, 1993), WO 2015/007903 A1 (22 January 2015) and Krippner-Heidenreich et al. (J. Immunol. 180(12):8176-8183, 2008) is withdrawn in view of amended claim 1 and Applicant’s argument.
Claim Rejections under 35 USC § 112 (a)
(i). The following is a quotation of the first paragraph of 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same and shall set forth the best mode contemplated by the inventor of carrying out his invention.
(ii). Claims 1, 8, 15, and 18-19 are rejected under 35 U.S.C. 112(a), as failing to comply with the written description requirement. The claim(s) contains subject matter, which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor at the time the application was filed, had possession of the claimed invention.
For each claim drawn to a genus, MPEP §2163 II.A.3(a) ii) (page 2100-189) states, “The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice (see i)(A), above), reduction to drawings (see i)(B), above), or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus (see i)(C), above). See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406”.
In the instant case, claim 1 recites a targeting moiety comprising a single-domain antibody, a recombinant heavy-chain-only antibody (VHH) or a single chain-chain antibody (scFv). Claim 1 does not require that the targeting moiety possess any particular conserved structural/functional features. The specification discloses hTNF mutants comprising Y87H/E146K or R32W/S86T, and the chimeric protein comprising the mutant and a targeting moiety, hCD20 nanobody (Example 1). The hTNF mutants comprising Y87H/E146K or R32W/S86T selectively bound to hTNF-R1 and exhibited significantly reduced or no binding to hTNF-R2 (page 112, lines 20-22). The chimeric protein comprising the hTNF-R1 mutant and hCD20 nanobody restored partially the activity of hTNF mutants toward hTNFR1 (Fig. 1, panels A-B; page 113, 9-13). On the other hand, the hTNF mutant comprising Y87H/A145R selectively bound to hTNF-R2 and exhibited significantly reduced or no binding to hTNF-R1 (page 112, lines 22-24). The chimeric protein comprising the hTNF mutant (Y87H/A145R) and hCD20 nanobody did not restore the affinity of the hTNF mutant (Y87H/A145R) for TNFR1 (Fig. 3, Panels A-B; page 113, lines 18-27). However, the specification does not disclose that targeting moieties other than hCD20 nanobody would restore the affinity of the modified human TNF-α for TNF-R1 but not TNF-R2.
Furthermore, the prior art does not provide compensatory structural or correlative teachings sufficient to enable one of skill to identify what other single-domain antibodies (targeting moieties) that bind to a marker on lymphocyte that express TNF-R1 and TNF-R2 and selectively restores the affinity of the modified human TNF-α for TNF-R1/TNF-R2 might be. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics for the targeting moieties, the specification does not provide sufficient support for the genus of targeting moieties, and thus the chimeric proteins.
(iii). Response to Applicant’s argument
Applicant argues that the specification provides ample guidance and support regarding the presently claimed chimeric protein. Applicant argues that the proof-of-concept experiments using an illustrative targeting moiety showed that the hTNF chimeric proteins comprising the Y87H/E146K mutation displayed far superior bioactivity and "reactivation by targeting" in the hTNF-R1 bioassay than the hTNF-R2 bioassay. Applicant argues that it is clear that Applicant was in possession of the claimed subject matter at the time of filing. Applicant’s argument has been fully considered but is not deemed to be persuasive for the reasons set forth in the rejection above.
Claim Rejections under 35 USC § 103(a)
(i). The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
(ii). Claims 1, 8, 15, and 18-19 are rejected under 35 U.S.C. 103(a) as being unpatentable over WO 2008/124086 A2 (October 16, 2008), and further in view of US patent No. 7,993,636 B2 (Date of Patent: Aug. 9, 2011), Barbara et al. (EMBO J. 13:843-50, 1994), WO 2015/007903 A1 (22 January 2015) and Krippner-Heidenreich et al. (J. Immunol. 180(12):8176-8183, 2008).
WO 2008/124086 A2 teach a chimeric protein comprising a modified human TNF-α, a linker, and a targeting moiety, wherein the modified human TNF-α comprises a mutation that reduces its binding affinity for its receptors ((Figure 1; page 3, lines 3-4 from the bottom; Example 3 on page 38). WO 2008/124086 A2 teaches that mutations S147Y and Y87H can be included in the modified human TNF-α (bottom of page 38 to top of page 39). The targeting moiety includes a single domain antibody (page 11, last paragraph) and targets a cell surface marker (page 14, last paragraph). Such a chimeric protein would avoid the toxicity while retaining desired activities as taught by WO 2008/124086 A2 (see, e.g., Abstract; Summary of the Invention).
WO 2008/124086 A2 does not explicitly teach (i) a modified human TNF-α comprising Y87H and E146K as recited in claim 1; and (ii) a trimeric single polypeptide chain having three copies of modified human TNF-α recited in claim 15.
US patent No. 7,993,636 B2 teaches TNF-α comprising one or more mutants, such as Y87H (see, e.g., Abstract; claim 1, lines 30-31).
Barbara et al. teach a human TNF-α comprising an E146K mutation that has reduced affinity to the p75TNF receptor (see e.g., Abstract).
WO 2015/007903 A1 teach a chimeric protein comprising a modified human TNF-α, a GGS linker, and a nanobody targeting moiety, wherein the modified human TNF-α has reduced activity and is a trimeric single polypeptide chain construct and comprises one or two mutations (Figure 1; Abstract).
Krippner-Heidenreich et al. teach a trimeric single polypeptide chain construct of the human TNF-α, which demonstrates both enhanced stability in vitro and in vivo and reduced toxicity in vivo, relative to the trimeric TNF (Abstract; page 8177, the 2nd paragraph of the left column).
It would have been obvious to one having ordinary skill in the art at the time the invention was made to make a chimeric protein comprising a modified human TNF-α that comprises Y87H and E146K with a reasonable expectation of success. One would have been motivated to do so because a modified human TNF-α that comprises such mutations would be expected to have a lower binding affinity for its receptors and a chimeric protein comprising such a modified human TNF-α avoid the toxicity while retaining desired activities as taught by WO 2008/124086 A2 (see, e.g., Abstract; Summary of the Invention).
It would also have been obvious to one having ordinary skill in the art at the time the invention was made to make a trimeric single polypeptide chain construct of the modified human TNF-α taught by WO 2015/007903 A1 and Krippner-Heidenreich et al. with a reasonable expectation of success. One would have been motivated to do so because teach a trimeric single polypeptide chain construct of human TNF-α offers enhanced stability and reduced toxicity as taught by Krippner-Heidenreich et al. above.
(iii). Response to Applicant’s argument
At the bottom of page 3 of Applicant’s response, Applicant argues that the Specification discloses that the hTNF mutant comprising Y87H/E146K exhibits reduced affinity for the hTNF-R1 receptor that is restored by attachment to an illustrative targeting moiety comprising a VHH.
Applicant’s argument has been fully considered but is not deemed to be persuasive because claim 1 and its dependent claims do not recite such a limitation-- reduced affinity for the hTNF-R1 receptor is restored by attachment to a targeting moiety; even if the claims recite the limitation, such a property would be inherent to the chimeric protein comprising a TNF-αmutant with Y87H/E146K and a nanobody.
In view of the extensive teachings by the cited art on making a chimeric protein comprising a modified human TNF-α, one would have been motivated to make a chimeric protein comprising a modified human TNF-α cited in claim 1 because such a chimeric protein would avoid the toxicity while retaining desired activities as taught by WO 2008/124086 A2 (see, e.g., Abstract; Summary of the Invention). Therefore, the claims must be rejected.
Conclusion
No claims are allowed.
Advisory Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Ruixiang Li whose telephone number is (571) 272-0875. The examiner can normally be reached on Monday through Friday from 8:30 am to 5:00 pm. If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Vanessa Ford, can be reached on (571) 272-0857. The fax number for the organization where this application or proceeding is assigned is (571) 273-8300.
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/RUIXIANG LI/Primary Examiner, Art Unit 1674 December 9, 2025