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 .
Election/Restrictions/Response to Amendment
Applicant’s amendment filed 02/17/2026 is acknowledged. Claim 64 is amended and claims 80-96 are new. Applicant’s election without traverse of the species of SEQ ID NO: 80 (the effector domain of deubiquitinase), SEQ ID NO 270 (the catalytic domain of deubiquitinase) and SEQ ID NO 271 in the reply filed on 02/17/2026 is acknowledged. All of the claims read upon the elected species. Claims 60-96 are under examination.
Effective Filing Date
Applicant’s claim for the domestic benefit of prior-filed applications under 35 U.S.C. 119(e) and 365(c) is acknowledged. No foreign priority claims are made. Under the AIA , the effective filing date of a claimed invention is the earlier of:
The actual filing date of the application;
OR
The filing date to which the application is entitled to a right of foreign priority or domestic benefit as to such claimed invention.
Note that with regard to claiming domestic benefit of prior-filed applications, MPEP 211.05 sets forth the disclosure requirements:
To be entitled to the benefit of the filing date of an earlier-filed application, the later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or earlier-filed nonprovisional application or provisional application for which benefit is claimed); the disclosure of the invention in the prior application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph, except for the best mode requirement. See Transco Prods., Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994). Accordingly, the disclosure of the prior-filed application must provide adequate support and enablement for the claimed subject matter of the later-filed application in compliance with the requirements of 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph, except for the best mode requirement.
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Based on the information given by Applicant and an inspection of the prior applications, the examiner has concluded that the subject matter defined in the instant claims 60-62, 65-86 and 88-96 is supported by the disclosure in provisional application serial no. 63110625 and PCT/US2021/058286. The prior applications do not support the recitation of “the amino acid sequence of the nuclear protein” in claims 63 and 87 or “the moiety that specifically binds a nuclear protein in claim 64. Therefore, the priority date of claims 60-96 of the instant application is 11/06/2020, while the priority date of claims 63, 64 and 87 is 05/04/2023.
Specification
The specification is objected to as failing to provide proper antecedent basis for the claimed subject matter. See 37 CFR 1.75(d)(1) and MPEP § 608.01(o). Correction of the following is required. Claims 63, 64 and 87 recite “the amino acid sequence of the nuclear protein” (claims 63, 87) and “the moiety that specifically binds a nuclear protein”. The specification, however, only mentions nuclear proteins once ([0032]), and does not disclose any amino acid sequences or moieties that bind a nuclear protein.
Claim Objections
Claims 83 and 93 are objected to because of the following informalities. Claim 83 lists “cytochrome c oxidase subunit 6A2” twice, which is redundant. Claim 93 is missing a period at the end of the claim. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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 63, 64, 67 and 89 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 63 and 87 recite the limitation “the amino acid sequence of the nuclear protein” and claim 64 recites the limitation “the moiety that specifically binds a nuclear protein”. There is insufficient antecedent basis for these limitations in the claim because claim 60, from which claims 63, 64 and 87 ultimately depend, does not make reference nuclear proteins, but rather, mitochondrial proteins. Further, claim 63 is confusing because it recites that the nuclear proteins comprise sequences set forth in SEQ ID NOs: 221-224 or 271-273, however, the instant specification defines these sequences as mitochondrial proteins (see paragraph [0022], for example).
Claim 89 recites the limitation “[t]he vector of claim 75”. There is insufficient antecedent basis for this limitation in the claim, since neither claim 74 or claim 75, from which claim 89 depends, recite a vector. Rather, independent claim 74 recites a fusion protein.
Claim Rejections - 35 USC § 112(a)
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.
Scope of Enablement
Claims 60-96 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the fusion proteins set forth in SEQ ID NOs: 243-269, the encoding nucleic acids, viral vectors comprising said nucleic acids and recombinant methods of making said proteins, does not reasonably provide enablement for the claims as broadly recited. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make or use the invention commensurate in scope with these claims.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.” (See In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 Fed. Cir. 1988) These factors include, but are not limited to: (a) the breadth of the claims; (b) the nature of the invention; (c) the state of the prior art; (d) the level of one of ordinary skill; (e) the level of predictability in the art; (f) the amount of direction provided by the inventor; (g) the existence of working examples; and (h) the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The claims are broad with respect to the recited effector/catalytic domains and targeting moieties. The independent claims encompass fragments and variants of the effector/catalytic domains. In addition, the claims recite sequences encompass up to 20% difference in sequence identities to the effector/catalytic domains and the proteins targeted by the targeting domains (see claims 61, 62, 85 and 86). The targeting moiety requires the function of specifically binding a mitochondrial protein and directing the effector domain to the target mitochondrial protein to mediate deubiquitination of the target mitochondrial protein. However, the structure of the targeting moiety is undefined in the claims, or defined as an antibody (claims 64 and 65). In addition, the mitochondrial protein which the targeting moiety binds is also undefined in most of the claims or recited only as a partial structure in the form of a recitation of percent identity. Thus, the claims encompass fusion proteins with specific functions but without sufficient structural limitations.
The number of mutations generally possible in any given protein that can be made with a reasonable expectation of success are limited. Certain positions in the sequence are critical to the protein's structure/function relationship, e.g., such as various sites or regions directly involved in binding, activity and in providing the correct three-dimensional spatial orientation of binding and active sites. As noted above, the claims require specific functions but encompass variants and fragments. The art provides evidence that mutations can be destabilizing and their effects unpredictable. Bhattacharya et al. (PLoS ONE 12(3): e0171355. https://doi.org/10.1371/journal.pone. 0171355; 22 pages total) teach even single nucleotide variations have a “range of effects at the protein level that are significantly greater than assumed by existing software prediction methods, and that correct prediction of consequences remains a significant challenge” (p. 18, 1st and 2nd paragraphs). In addition, Fenton et al. (Medicinal Chemistry Research (2020) 29:1133–1146) review the unpredictability of making substitutions at non-conserved positions in a protein, which can have significant effects on protein function, that computational algorithms cannot predict very well (p. 1134, right column, middle paragraph).
Although machine learning algorithms have improved the ability to predict protein 3D structure from sequences, methods based on artificial intelligence for predicting the impact of mutations on protein stability still face challenges, including prediction biases towards “generalization”, “data set”, “destabilizing mutations” and the inability to predict the effects of multiple mutations. See Figure 1, at p. 162 and the discussion at pages 165-166 of Pucci et al. (Current Opinion in Structural Biology 2022, 72: 161-168). Even in the case of single mutations, artificial intelligence programs do not accurately “predict the impact of mutation on protein stability” or function (see p. 2, 2nd paragraph and p. 7, 1st full paragraph of Pak et al., PLoS ONE 18(3): e0282689. https://doi.org/10.1371/ journal.pone.0282689).
Further, the claims encompass up to a 20% divergence from the recited sequences. Applicants have provided little or no guidance beyond the mere presentation of sequence data to enable one of ordinary skill in the art to determine, without undue experimentation, the positions in the protein which are tolerant to change by amino acid substitutions or deletions, and the nature and extent of changes that can be made in these positions. Although the specification outlines art-recognized procedures for producing and screening for active muteins, this is not adequate guidance as to the nature of active derivatives that may be constructed, but is merely an invitation to the artisan to use the current invention as a starting point for further experimentation.
Claims 71 and 79 encompass treating and preventing disease, for instance, genetic diseases. The instant specification discloses an in vitro screening assay for testing fusion proteins (see paragraphs [00215]-[00220]). The results of the screening assay are shown in Figures 3-5 of the instant application, namely, the tested fusion proteins were capable of increasing COX6A2, UQCC2 and LYRM7 (all mitochondrial proteins) expression. Nevertheless, these data do not support treating, let alone preventing disease. Genetic diseases may arise from de novo or inherited loss of function mutations (see paragraph [0077] of the instant specification), thus, they cannot be prevented with the claimed methods since it is not known who will develop these diseases. The guidance in the instant specification present data that certain specific fusion proteins increase mitochondrial protein expression in vitro, but there is no guidance suggesting they could prevent any genetic disease or haplo-insufficiencies from occurring.
Compounding the breadth of the recited fusion proteins and their encoding nucleic acids, the specification contemplates gene therapy (see paragraphs [00192]; [0201]) with the encompassed nucleic acids encoding the fusion proteins, however, the instant specification does not teach any gene therapy working examples. Relevant literature teaches despite having made strides over the past 40 years, gene therapy remains unpredictable (see Antoine Gardin and Giuseppe Ronzitti, Archives de Pédiatrie 30 (2023) 8S46–8S52—hereafter “Gardin”). Gardin teaches that while methods of using adeno-associated viral (AAV) vectors for transducing DNA have improved, particularly in the treatment of the liver, central nervous system, muscles, eye and bone marrow, significant challenges remain (see p. 8S46, left column, 1st paragraph). For instance, besides immunogenicity, challenges include non-target organ effects, the neutralizing effect of autoantibodies and loss of long-term correction (see p. 8S48, left column, 2nd paragraph; paragraph bridging pages 8S48-8S49; p. 8S49, under “3”). In view of the teachings of the relevant art, the ability to treat genetic diseases comprising DNA-based therapies was not readily available in the relevant art at the time of filing of the instant application, and the limited teachings of the instant application do not overcome these shortcomings.
Due to the large quantity of experimentation necessary to determine whether the encompassed fusion proteins/encoding nucleic acids are capable of the required functions, including treatment and prevention of genetic diseases, the lack of direction/guidance presented in the specification regarding and the absence of working examples directed to the same, the complex nature of the invention, the unpredictability of the effects of mutation on protein structure and function, and the breadth of the claims which fail to recite limitations on the fusion proteins and their encoding nucleic acids, undue experimentation would be required of the skilled artisan to make and/or use the claimed invention in its full scope.
Written Description
Claims 60-96 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a written description rejection.
The claims recite fusion proteins comprising effector and catalytic domains and targeting moieties and the encoding nucleic acids. The independent claims encompass fragments and variants of the effector/catalytic domains. In addition, the claims reciting sequences encompass up to 20% difference in sequence identities to the effector/catalytic domains and the proteins targeted by the targeting domains (see claims 61, 62, 85 and 86). The targeting moiety requires the function of specifically binding a mitochondrial protein and directing the effector domain to the target mitochondrial protein to mediate deubiquitination of the target mitochondrial protein. Claims 71 and 79 encompass treating and preventing disease, for instance, genetic diseases. Thus, the claims encompass fusion proteins with specific functions but without sufficient structural limitations.
The MPEP 2163(A) states “‘[a]n invention described solely in terms of a method of making and/or its function may lack written descriptive support where there is no described or art-recognized correlation between the disclosed function and the structure(s) responsible for the function.’” For inventions in emerging and unpredictable technologies, or for inventions characterized by factors not reasonably predictable which are known to one of ordinary skill in the art, more evidence is required to show possession. (See MPEP 2163(II)(A)(3)(a)(i)). To provide 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 the claimed product, or any combination thereof.
In deciding whether the application complies with the written description requirement of 35 USC 112(a) or 35 USC 112 (pre-AIA ), first paragraph, it is necessary to understand what Applicant is claiming (see above) and Applicant has possession of. From the specification, it is clear that Applicant has possession of the fusion proteins set forth in SEQ ID NOs: 243-269 (see Table 6 at paragraph [00212]). These 27 fusion proteins, however, are not representative of the genus of fusion protein variants and fragments that may differ by up to 20% from the recited sequences. Further, the structure of the targeting moiety is undefined in the claims, or defined as an antibody (claims 64 and 65). In addition, the mitochondrial protein which the targeting moiety binds is also undefined in most of the claims or recited only as a partial structure in the form of a recitation of percent identity.
Insomuch as the targeting moiety reads upon an antibody or VHH, it is well established in the art that the formation of an intact antigen-binding site generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs which provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin. The prior art teaches that small changes in the amino acid structure of the CDRs can have large effects on activity. For instance, Piche-Nicholas et al. (MAbs. 2018; 10: 81-94. doi: 10.1080/19420862.2017.1389355) teaches that the “binding affinity of IgG Molecules…to FcRn that differed by only a few amino acid residues in CDRs revealed that small changes in CDRs, as minute as one amino acid residue change, could alter affinity to FcRn up to 79-fold.” See p. 89, right column, last paragraph of Piche-Nicholas et al. In summary, the claims only recite a catalytic/effector domain, a targeting moiety, an antibody, a VHH, and a protein to which the moiety is targeted. Further, the protein is undefined or described only as a partial structure in the form of a recitation of percent identity. 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). With the exception of SEQ ID NOs: 243-269, the skilled artisan cannot envision the detailed chemical structure of the encompassed fusion proteins and their encoding nucleic acids, 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 it is part of the invention and reference to a potential 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, only fusion proteins set forth in SEQ ID NOs: 243-269 and their encoding nucleic acids, but not the full breadth of the claim meets the written description provision of 35 U.S.C. §112, first paragraph. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115).
Notice for all US Patent Applications filed on or after March 16, 2013: 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.
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 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 60, 66-70, 74-78, 80-82, 89 and 91 are rejected under 35 U.S.C. 103 as being unpatentable over Colecraft (WO2019/090234; published 05/09/2019—on IDS filed 03/11/2024) in view of Wenz (EP2992892; published 09/05/2014). The first factor to consider when making a rejection under 35 U.S.C. 103(a) is to determine the scope and contents of the prior art. 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 as well as the nucleic acid encoding the recombinant DUB and adenoviral vectors (claim 1; paragraphs [0009]-[0010]; [0063]-[0065]), thereby teaching limitations of claims 60, 66, 67, 74, 75, 80, 81, 89 and 91. Colecraft teaches that excessive ubiquitination is associated with inherited disorders and that deubiquitinases (DUBs) remove ubiquitin (see paragraphs [0005]-[0006]). Colecraft developed a DUB for screening and treating disease (see paragraphs [0010]-[0012]; [0039]-[0040]). Colecraft teaches how to produce the proteins recombinantly (see paragraphs [0052]-[0053]), thereby teaching limitations in claims 68, 70, 76 and 78.
The second factor to consider is to ascertain the differences between the prior art and the instant claims. Colecraft does not teach that the protein binder in (b) binds a mitochondrial protein. Wenz teaches a fusion protein and the encoding nucleic acid and vector comprising said nucleic acid that comprises a) a protein transduction domain, and a mitochondrial targeting sequence in order to treat by “mitochondrial protein replacement therapy (claims 1, 7, 9; paragraphs [0053]-[0055]). Wenz teaches that the mitochondrial targeting sequences and fusion proteins may be formulated as a pharmaceutical composition comprising an acceptable carrier (paragraphs [0044]-[0046]), thereby teaching limitations in claims 60, 69, 74, 77, 81 and 82.
It would have been obvious to the person of ordinary skill in the art at the time of the filing of the invention to modify the teachings of Colecraft by using the mitochondrial targeting sequences of Wenz in the engineered DUB because there are many conditions associated with mitochondrial dysfunction and “[i]t would be beneficial to have a platform for high throughput screening of…disease-causing mutations to diagnose underlying pathological mechanisms” (see paragraph [0007] of Colecraft and paragraph [0003] of Wenz). The person of ordinary skill in the art would have been motivated to adapt the screening platform developed by Colecraft to investigate mitochondrial dysfunction because Wenz teaches that conditions resulting from mitochondrial dysfunction have no treatment options other than symptom management (see paragraph [0003] of Wenz). Furthermore, the person of ordinary skill in the art could have reasonably expected success because Wenz teaches that their fusion protein successfully targeted the mitochondria in vitro and in vivo (see Examples 3-4; paragraphs [0067]-[0080].
Thus, the claims do not contribute anything non-obvious over the prior art.
Conclusion
No claim is allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. The international search report listed Zhang (WO2019/126762—on IDS filed 03/11/2024), which describes using Cpf1 as an effector protein in a Crispr/Cas system (see claims). Further, Briston et al. (Biochemical Society Transactions (2018) 46 829-842—on IDS filed 02/17/2026) was listed in a search report and discusses the involvement of deubiquitinase in neurodegenerative diseases (see paragraph bridging pages 836-837). However, neither reference teaches or suggests the instantly claimed fusion proteins.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRISTINA M BORGEEST whose telephone number is (571)272-4482. The examiner can normally be reached M-F 9-5:30 EDT.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Stucker can be reached at 5712720911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CHRISTINA M BORGEEST/Primary Examiner, Art Unit 1675
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