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
The Information Disclosure Statements (IDS) filed 4 May 2023, 27 February 2024, and 2 February 2026 have been entered. Applicant’s amendments of the specification filed 4 May 2023 and 27 February 2024 have been entered. Applicant’s amendment of the claims filed 2 February 2026 has been entered.
Election/Restriction
In the response received on 2 February 2026, Applicant elected, without traverse, the invention of Group I, claims 95-104, 107 and 112, and the species of: A) wherein the amino acid sequence of the effector domain comprises SEQ ID NO: 80 (OTU7B/Cezanne); B) wherein the amino acid sequence of the catalytic domain comprises SEQ ID NO: 293 (OTU7B/Cezanne); and C) wherein the amino acid sequence of the membrane protein comprises SEQ ID NO: 294 (sugar transporter SWEET1 (SLC50A1)).
Claims 1-94, 105-106, 108-111 and 113-114 are cancelled. Claims 115-126 have been added. Claims 95-104, 107, 112 and 115-126 are pending and under examination to the extent they read on the elected species. Claims 95-104 and 115-126 read on the elected species, and claims 107 and 112 are withdrawn as being drawn to non-elected species.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Objections
Claim 97 is objected to because of the following informalities:
Claim 97 recites “any one of SEQ ID NOS: 113-220, 129, or 293”. SEQ ID NO: 129 is included in SEQ ID NOS: 113-220.
Appropriate correction is required.
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.
Claims 118-119 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 118 depends from claim 95 and recites “wherein the cytosolic protein is titin”. Claims 119 depends from claim 118 and recites “wherein the antibody comprises a VHH”. There is insufficient antecedent basis for the limitations in the claims.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph 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.
The following is a quotation of the first paragraph of pre-AIA 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.
Claims 95-104 and 115-126 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claims contain 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, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Independent claim 95 recites “A nucleic acid molecule encoding a fusion protein comprising: (a) an effector domain comprising a catalytic domain of a deubiquitinase, or a functional fragment or functional variant thereof, operably connected to (b) a targeting domain comprising a targeting moiety that specifically binds a membrane protein that is not an ion channel.” Depending claims further limit wherein the amino acid sequence of the effector domain or the catalytic domain is at least, e.g., 80%, identical to the SEQ ID NOs listed in claims 96-97 (e.g., the amino acid sequence of the effector domain is at least 80% identical to SEQ ID NO: 80, and the amino acid sequence of the catalytic domain is at least 80% identical to SEQ ID NO: 293); wherein the amino acid sequence of the membrane protein is at least, e.g., 90%, identical to the SEQ ID NOs listed in claim 98 (e.g., the amino acid sequence of the membrane protein is at least 90% identical to SEQ ID NO: 294); and wherein the moiety that specifically binds a membrane protein comprises an antibody, or functional fragment or functional variant thereof (claim 99).
The claims are broad and encompass nucleic acids encoding a broad genus of fusion proteins comprising: (a) an effector that comprises a catalytic domain of a deubiquitinase, or a functional fragment or functional variant thereof; and (b) a targeting domain that comprises a targeting moiety that specifically binds to any non-ion channel membrane protein, or any variant of the membrane proteins set forth in SEQ ID NOs: 221-227, 243-245 and 295. The specification, however, fails to provide adequate written description and evidence of possession of these molecules.
Regarding the “effector domain”, the specification describes human deubiquitinases and the catalytic domains comprised therein (see Table 1), which include human deubiquitinases set forth in SEQ ID NOs: 1-112, and the catalytic domains comprised therein set forth in SEQ ID NOs: 113-220 and 293. Except for the full-length human deubiquitinases and the catalytic domains comprised therein, the specification does not provide adequate written description for the “functional fragment or functional variant thereof”, nor the variant effector domains/catalytic domains having at least 80% identical to the amino acid sequences of SEQ ID NOs 1-112, 113-220, 293 and 447. The specification does not provide sufficient teachings regarding the correlation of structure to function, such as what changes can be made without destroying the catalytic activity or other function of the protein. It is well known in the art that even minor changes in sequence can result in major changes in function, especially if the minor sequence change occurs within an active site or alters the overall conformation of the molecule. For example, Olazabal-Herrero et al. (FEBS J., 2016, Vol. 283:929–946) studied mutations in the USP1 Fingers subdomain, and found that although USP1 deubiquitinase activity is crucially dependent on the interaction with UAF1 via the USP1 Fingers subdomain, mutations in the Fingers subdomain abrogated substrate deubiquitination without interfering with other USP1 activities, such as UAF1 binding or autocleavage. It is unpredictable how mutation(s) may affect the function(s) of a protein. In the absence of sufficient description of distinguishing identifying characteristics, the skilled artisan cannot envision the detailed structures of the encompassed effector domains as claimed.
Regarding the “targeting domain”, the claims, as written, encompass the use a targeting moiety that specifically binds to any non-ion channel membrane protein, or to any variant of the membrane proteins set forth in SEQ ID NOs: 221-227, 243-245 and 295. These targeting moieties can be, e.g., a ligand, a peptide, an interacting protein, an antibody, etc.. The specification fails to adequately describe the broad scope of the targeting moieties, and there is no representative number of species disclosed. For example, Liu et al. (J. Cell. Mol. Med., 2021, Vol. 25(24):11113-11127) newly identified soluble TREM-1 (sTREM-1) as a new ligand for the membrane receptor Robo2 (see abstract). With regard to the antibodies or antigen-binding fragments, while the specification describes that the targeting moiety may comprise an antibody, a scFv, a (scFv)2, a scFv-Fc, a Fab, a Fab′, a (Fab′)2, a F(v), a single domain antibody, a single chain antibody, a VHH, or a (VHH)2, the specification, however, fails to teach the structures of these molecules. The specification provides exemplary target binders in Table 4, which includes: YFP targeting nanobody (SEQ ID NO: 255), b-2 adrenergic receptor human binder (monobody) (SEQ ID NO: 256), k-type opioid receptor human binding (monobody) (SEQ ID NO: 257), and muscarinic acetylcholine receptor M2 human (monobody) (SEQ ID NO: 258). The specification further provides exemplary fusion proteins between the listed target binder and an effector domain (e.g., Cezanne, OTUD1, TRABID, USP21, OTUD4, human USP3 set forth in SEQ ID NOs: 259-264, respectively) (see Table 5). Except for the targeting domains set forth in SEQ ID NOs: 255-258, the specification does not adequately describe the structures of the broad scope of targeting domains that comprise a targeting moiety specifically binding to a membrane protein. It is well established in the art that the formation of an intact antigen-binding site generally requires the association of the complete heavy chain and light chain variable regions of a given antibody, each of which includes three CDRs or hypervariable regions which provide the majority of the contact residues for the binding of the antibody to its target epitope. Even for a single epitope, there could be numerous antibodies that have distinct antigen-binding domains. For example, Nair et al. (2002, J. Immunol., Vol. 168(5):2371-2382) teaches that monoclonal antibodies that bind to the same epitope have dissimilar binding site structures, and the dissimilarity is primarily expressed in the conformations of the CDR-H3, which is responsible for defining the epitope specificity (see Abstract). The prior art does not teach how to predict the structures of the antibodies or antigen-binding fragments that bind to a disclosed epitope, let alone a full-length protein. Further, a skilled artisan cannot envision the detailed structures of those targeting domains that can direct an effector domain to the target protein and mediate deubiquitination of the target membrane protein, as required by the claims. In Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017), the Federal Circuit explained that when an antibody is claimed, 35 U.S.C. § 112(a) requires adequate written description of the antibody itself. The specification fails to provide adequate written description and evidence of possession of the broad scope of the targeting domain/targeting moiety as claimed.
To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making of the claimed product, or any combination thereof. In this case, there is no sufficient teachings regarding the structural characteristics of the genus, nor the correlation of structure to function. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116). As discussed above, the skilled artisan cannot envision the detailed structures of the encompassed genus of molecules, and therefore, conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that is part of the invention and reference to a method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence.
Therefore, except for nucleic acid molecules encoding a fusion protein comprising: (a) an effector domain comprising a catalytic domain of a human deubiquitinase or comprising the amino acid sequence set forth in any of SEQ ID NOs: 221-227, 243-245 and 295, operably connected to (b) a targeting domain comprising a targeting moiety that comprises the amino acid sequence set forth in any of SEQ ID NOs: 255-258, there is no adequate written description for the full scope of the claimed molecules.
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 of this title, 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.
Claims 95-104, 115-117, 120-121, 123-126 are rejected under 35 U.S.C. 103 as being unpatentable over Colecraft et al. (WO 2019/090234 A1, Int.’l Pub. Date: 9 May 2019), in view of Gazzerro et al. (Am. J. Pathol., 2010, Vol. 176(4): 1863-1877), and further in view of Kunkel et al. (U.S. Patent No. 5,541,074, Date of Patent: Jul. 30, 1996).
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
Colecraft teaches that integral surface membrane proteins including ion channels, transporters, and receptors are vital to the survival and function of all cells; consequently, processes that control the surface abundance and composition of membrane proteins are critical determinants of cellular biology and physiology [0004]. Colecraft teaches that ubiquitination has classically been ascribed to targeting cytosolic proteins for degradation by the proteasome; in contrast, ubiquitination of membrane proteins can lead to more nuanced outcomes including regulating protein trafficking/sorting, stability, and/or function, and ubiquitination of membrane proteins has been found to be associated with inherited disorders and infectious diseases [0005]. Colecraft teaches that deubiquitinases (DUBs) provide salience to ubiquitin signaling through the revision and removal of ubiquitin chains [0006]. Colecraft teaches a recombinant engineered deubiquitinase (DUB) comprising: a) a catalytic unit; b) a protein binder; and c) a variable linker between the catalytic unit and the protein binder, and a nucleic acid encoding same, that can be used to target ubiquitination of a protein, thereby treating a disorder or disease associated therewith [0009] [0010]. Colecraft teaches that the catalytic unit comprises the catalytic domain of a deubiquitinase, e.g., Cezanne (corresponding to SEQ ID NO: 80 of the instant application, see sequence alignment attached) [0029]. Colecraft teaches that the protein binder of the recombinant engineered DUB is selected from intracellular antibody fragments, scFvs, nanobodies, antibody mimetics, monobodies, DARPins, lipocalins, and targeting sequences [0030]. Colecraft also teaches a recombinant vector or adenoviral vector comprising a nucleic acid that encodes the recombinant engineered DUB, and a cell transformed with the vector for recombinant protein expression [0013].
Colecraft teaches as set forth above. Colecraft, however, does not teach wherein the protein binder specifically binds to a membrane protein (claim 95) that comprises an amino acid sequence at least 90% identical to any one of SEQ ID NOs: 221-227, 243-245 and 294 (claim 98).
Gazzerro teaches that the pathologies of Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are caused by deficiency or a reduction in the amount of dystrophin protein (corresponding to SEQ ID NO: 227 of the instant application) (p. 1863, col. 2). Gazzerro teaches that blocking ubiquitin-mediated protein degradation of dystrophin has the therapeutic potential for treatment of DMD and BMD (see Abstract).
Kunkel further teaches antibodies and antigen-binding fragments thereof that specifically bind to dystrophin.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to prepare a recombinant engineered deubiquitinase (DUB) as taught by Colecraft by using an antibody or antigen-binding fragment thereof that specifically binds to dystrophin. One of ordinary skill in the art would have been motivated to do so, because Colecraft teaches a recombinant engineered deubiquitinase (DUB) comprising: a) a catalytic unit; b) a protein binder; and c) a variable linker between the catalytic unit and the protein binder, and a nucleic acid encoding same, that can be used for revising or removing ubiquitination of a protein, thereby treating a disorder or disease associated therewith, Gazzerro further teaches that DMD and BMD are associated with ubiquitin-mediated protein degradation of dystrophin, and blocking ubiquitin-mediated protein degradation of dystrophin has therapeutic potential for treatment of the diseases, and Kunkel furthermore teaches an antibody and antigen-binding fragment thereof that can be used as a protein binder for specifically binding to dystrophin. Therefore, the combined teachings provide a reasonable expectation of success in making a recombinant engineered deubiquitinase (DUB) for a therapeutic use.
Conclusion
NO CLAIM IS ALLOWED.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Xiaozhen Xie, whose telephone number is 571-272-5569. The examiner can normally be reached on M-F, 8:30-5.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Vanessa L. Ford, can be reached on 571-272-0857. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/XIAOZHEN XIE/Primary Examiner, Art Unit 1674
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