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
Application status
Claims 19-29, 32, 34-36 and 38-42 are pending in this application.
Priority
It is acknowledged that the instant application is a CON of PCT/US2022/0125700 filed on 01/14/2022, which claims benefit of 63137419 filed on 01/14/2021.
Election
Applicants' election without traverse of Group I, Claims 19-25 and 38-42, and species CD8, cytokine, ADAM17 protease cleavage site, IKF3/ZFP91/IKZF3, pomalidomide, and d913, in the response filed on 07/31/2026, is acknowledged.
Claims 26-29, 32 and 34-36 are withdrawn from further consideration by the Examiner, 37 CFR 1.142(b) as being drawn to a non-elected invention.
For the reasons provided above, this restriction requirement is deemed proper, and therefore, it is made final.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 09/03/2025 and 01/22/2026 are acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Claim Rejections - 35 U.S.C. § 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.
Claims 20-21 are rejected under 35 U.S.C. § 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
Claim 20 recites the phrase, “a synthetic promoter” which is indefinite. The ‘metes and bounds’ of the noted phrase is unclear because [1] while the word "synthetic" itself has a reasonably precise meaning (i.e., man-made, non-naturally occurring), a promoter's exact sequence determines its function, simply claiming "a synthetic promoter" without structural or strict functional boundaries creates an unclear claim scope; and [2] the instant specification does not define the noted phrase. In the interest of advancing prosecution, the noted phrase is interpreted as “any promoter”.
Claim 21 recites the phrase “optimized IL2” which is indefinite. The ‘metes and bounds’ of the noted phrase is unclear because [1] it is unclear to what structural/functional changes must be made to IL2 in order for it to be within the scope of “optimized IL2”; and [2] the instant specification does not define the noted phrase. In the interest of advancing prosecution, the noted phrase is interpreted as “any IL2”.
The following is a quotation of 35 U.S.C. 112(a):
(a) IN GENERAL.—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 or joint inventor of carrying out the invention.
Claims 19-25 and 38-42 are rejected under 35 U.S.C. § 112(a), written description, 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(s), at the time the application was filed, had possession of the claimed invention.
The instant claims are directed to an engineered nucleic acid comprising an expression cassette comprising a promoter and an exogenous polynucleotide sequence encoding a membrane- cleavable chimeric protein, oriented from N-terminal to C-terminal, having the formula: S-C-MT-D wherein S comprises a secretable effector molecule, C comprises a protease cleavage site, MT comprises a cell membrane tethering domain, and D comprises a degron, wherein the promoter is operably linked to the exogenous polynucleotide sequence, and wherein S-C-MT-D is configured to be expressed as a single polypeptide.
To satisfy the written description aspect of 35 U.S.C. § 112(a) for a claimed genus of [compositions or methods], it must be clear that: (1) the identifying characteristics of the claimed [compositions or methods] have been disclosed, e.g., structure, physical and/or chemical characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or a combination of these; and (2) a representative number of species within the genus must be disclosed.
The Court of Appeals for the Federal Circuit has recently held that a “written description of an invention involving a chemical genus, like a description of a chemical species, ‘requires a precise definition, such as be structure, formula [or] chemical name,’ of the claimed subject matter sufficient to distinguish it from other materials.” University of California v. Eli Lilly and Co., 1997 U.S. App. LEXIS 18221, at *23, quoting Fiers v. Revel, 25 USPQ2d 1601, 1606 (Fed. Cir. 1993) (bracketed material in original). To fully describe a genus of genetic material, which is a chemical compound, applicants must (1) fully describe at least one species of the claimed genus sufficient to represent said genus whereby a skilled artisan, in view of the prior art, could predict the structure of other species encompassed by the claimed genus and (2) identify the common characteristics of the claimed molecules, e.g., structure, physical and/or chemical characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or a combination of these (paraphrased from Enzo Biochemical Inc. v. Gen-Probe Inc. (CAFC (2002) 63 USPQ2d 1609).
The genus of claimed composition is so broad as to encompass any engineered nucleic acids encoding any single polypeptide membrane-cleavable chimeric protein of the formula S-C-MT-D, wherein S comprises any secretable effector molecules, C comprises any protease cleavage sites, MT comprises any cell membrane tethering domains, and D comprises any degrons, operably linked to any promoters. However, the specification discloses only a few representative species of the claimed genus, i.e. an engineered nucleic acid encoding Secreted Alkaline Phosphatase (SEAP) or IL-10 (limited IL-15/IL-12 data) fused to ADAM10/17 cleavage site fused to a PDGFRβ transmembrane domain fused to CRBN-based degrons including d913 and SEQ ID NO: 189, that responds to lenalidomide. The specification fails to describe a representative number of species spanning the enormous structural and functional diversity of the claimed S, C, MT, and D elements oriented any order, nor does it disclose a structure to function correlation between all possible variations, combinations and/or orientation of any and all S, C, MT and D elements, such that a person of ordinary skill in the art would recognize that the inventors were in possession of the full genus of “any engineered nucleic acids” as noted above.
In conclusion, the genus of “any engineered nucleic acids” encompasses widely variant species, having essentially any structure. While M.P.E.P. section 2163 acknowledges that a single species can describe a genus, it also acknowledges that for a genus that encompasses widely variant species, disclosure of a single species within the genus fails to adequately describe all members of the genus. Please refer to the M.P.E.P. section 2163.05 [R-7.2022] under I, B for more details with respect to sufficient number of representative species that should be disclosed to describe a widely variant genus.
Given the lack of additional representative species of the claimed genus of “any engineered nucleic acids”, Applicants have failed to sufficiently describe the claimed invention, in such full, clear, concise, and exact terms that a skilled artisan would recognize Applicants were in possession of the claimed invention.
Applicant is referred to the revised guidelines concerning compliance with the written description requirement of U.S.C. 112(a) published in the Official Gazette and also available at www.uspto.gov.
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.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 19-25 and 38-42 are rejected under 35 U.S.C. 103 as being unpatentable over Hinrichs et al. (WO2019/157130) in view of Scheller et al. (ADAM17: a molecular switch to control inflammation and tissue regeneration, Trends in Immunology, August 2011, Vol. 32, No. 8, pg 380-387), Jan et al. (WO2019/089592, see IDS), and KSR International Co. v. Teleflex Inc., 550 U.S.--, 82 USPQ2d 1385 (2007).
The instant claims are drawn to an engineered nucleic acid comprising an expression cassette comprising a promoter and an exogenous polynucleotide sequence encoding a membrane- cleavable chimeric protein, oriented from N-terminal to C-terminal, having the formula: S-C-MT-D wherein S comprises a secretable effector molecule, C comprises a protease cleavage site, MT comprises a cell membrane tethering domain, and D comprises a degron, wherein the promoter is operably linked to the exogenous polynucleotide sequence, and wherein S-C-MT-D is configured to be expressed as a single polypeptide.
Hinrichs et al. teach an engineered nucleic acid, i.e., recombinant expression vector, comprising a promoter, and nucleic acids encoding a membrane-tethered cytokine of S-MT structure, wherein S is IL15 or IL21, and MT is CD8 transmembrane sequence of SEQ ID NO: 4 and other Type-I transmembrane anchors (see claims and Talbe 1; Figs. 1A-1B), and wherein S-MT is configured to be expressed as a single polypeptide. Hinrichs et al. further teach the use of a human IgE signal sequence, i.e., non-native, fused to IL-15/IL21 (see Table 1 on pg 27), which reads on claim 21.
Hinrich et al. do not teach C comprising a protease site, and D comprising a degron.
Scheller et al. teach ADAM17/TACE which cleaves membrane-tethered cytokines and receptors immediately proximal to the plasma membrane and releases a soluble ectodomain (see Abstract and Figure 2 on pg. 382).
Jan et al. teach a fusion of CRBN polypeptide substrate domain (IKZF1, IKZF3, and chimeric IKZF3/ZFP91/KCZF3, d913-lineage degron) to a protein of interest in engineered immune cells, conferring IMiD such as lenalidomide- or pomalidomide-dependent CRBN binding and ubiquitin-mediated degradation (see all claims; all Figures and related discussions). Jan et al. further teach that the chimeric IKZF3/ZFP91/KCZF3 comprises the amino acid sequence of SEQ ID NO: 95, which is 100% identical to Applicants’ SEQ ID NO: 189 (see page 30).
It would have been obvious to a person of ordinary skill in the art (POSITA) prior to the effective filing date of the instant application to make and use the engineered nucleic acid by Hinrichs et al. and add C taught by Scheller et al. with D taught by Jan et al. to make S-C-MT-D oriented from N- to C-terminus. A POSTIA would have been motivated to make and use such composition because [1] membrane-tethered cytokines on activated immune cells are already known to be shed by ADAM17, i.e., by inserting an ADAM17 cleavage site between the cytokine and the TM domain, which allows for protease-triggered release when the engineered cell is activated (the same cellular state in which ADAM17 is upregulated on T/NK cells), which in turn provides the benefit of releasing permanently tethered payload into a locally releasable payload; [2] permanent membrane-tethered cytokines are known toxicity risk, and teachings of Jan et al. provide an “OFF switch”, i.e., an IMiD-responsive CRBN degron already shown to work on proteins expressed in engineered T cells, using lenalidomide or pomalidomide; and [3] Type I TM domains have a cytoplasmic C-terminus, which would be the only place to put the degron taught by Jan et al. without disrupting extracellular releasable payload structure.
As discussed in KSR International Co. v. Teleflex Inc., 550 U.S.--, 82 USPQ2d 1385 (2007), it is considered obvious to combine prior art elements known to be used in equivalent fields of endeavor together into a single combination. The combination of references clearly shows that it is not a random mix of two technologies. Rather, it is a predictable next step on the same composition, i.e. immune cells expressing tethered cytokines combining it with a known protease cleavage site of ADAM17 to unload cytokine payloads locally with a known IMiD degron ‘Off Switch’ to prevent toxicity.
A POSITA would have had a reasonable expectation of success to make and use such composition because all of the required biochemical reagents and techniques were readily available and rampantly used as evidenced by Hinrichs al., Scheller et al. and Jan et al. prior to the filing of the instant application.
For the reasons provided herein, the invention as claimed is prima facie obvious over the combined teachings of the prior art.
Conclusion
Claims 19-25 and 38-42 are rejected for the reasons as stated above. Applicants must respond to the objections/rejections in this Office action to be fully responsive in prosecution.
The instant Office action is non-final.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JAE W LEE whose telephone number is (571)272-9949. The examiner can normally be reached on M-F between 9:00-6:00.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Manjunath Rao can be reached on (571)272-0939. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JAE W LEE/
Examiner, Art Unit 1656
/MANJUNATH N RAO/Supervisory Patent Examiner, Art Unit 1656
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