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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 filed on 04/08/2026 has been entered.
Status of Claims
Claims 1-9, 11-14, and 19-20 are cancelled.
Claims 10, 15-18, and 21-29 are pending and examined herein.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or
under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. This application claims benefit of
the application of 63/155,580 filed 03/02/2021. Based on the filing receipt, the effective filing
date of this application is March 2, 2021 which is the filing date of Application Number
63/155,580 from which the benefit of priority is claimed.
Withdrawn Rejections
The 35 U.S.C. 103 rejections of claims 1-4, 6-9, and 19-20 have been withdrawn, due to the amendments filed 04/08/2026 which cancelled the claims.
The rejections of claims 10 and 15-16 on the grounds of 35 U.S.C. 103 have been withdrawn, due to amendments filed 04/08/2026. In the amendments, independent claim 10 has been amended to recite, “wherein the active phosphodiesterase (PDE) domain and the active ADP-ribosyltransferase (ART) domains are provided in separate polypeptides”.
The rejection of claim 17 on the grounds of 35 U.S.C. 103 has been withdrawn, due to amendments filed 04/08/2026. In the amendments, independent claim 17 has been amended to include sequential steps of a method requiring separate ART and PDE domains. See claim interpretation below.
Claim Interpretation
Steps a)-c) of claim 17 are interpreted as sequential, due to the disclosure of the declaration under 37 C.F.R. 1.132 by Dr. Vincent S. Tagliabracci filed 04/08/2026. In the case where steps a) and b) are simultaneous, claim 17 would encompass methods where the ADP-ribosyltransferase domain and the phosphodiesterase domain of the SidE-ligase protein are contained within one enzyme. However, the declaration discloses that the two domains must be separate to be operable in the claimed invention. In the declaration, Tagliabracci discloses, “the claimed assay requires a pre-ADP-ribosylated construct to be available for interaction with the target protein before PDE-mediated covalent linkage is carried out. When the pre-ADP ribosylated construct is not used, any active ART domain present uses added NAD+ to ADP-ribosylate ubiquitin inefficiently to Ub-ADPR, which is then quickly converted to Ub-pR by the PDE domain, resulting in a bait that is unable to capture the target” (see, para. 9 of the declaration).
New Rejections
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 10, 15-18, and 21-29 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 inventors, at the time the application was filed, had possession of the claimed invention.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include: (1) Actual reduction to practice, (2) Disclosure of drawings or structural chemical formulas, (3) Sufficient relevant identifying characteristics (such as: i. Complete structure, ii. Partial structure, iii. Physical and/or chemical properties, iv. Functional characteristics when coupled with a known or disclosed, and correlation between function and structure), (4) Method of making the claimed invention, (5) Level of skill and knowledge in the art, and (6) Predictability in the art. See MPEP 2163.
Claim 10 is directed to a system for proximity-based labeling of a biomolecule comprising a genetically modified ubiquitin. The claim imposes no restriction on the size of the genetically modified ubiquitin or the degree of modification.
The scope of the claims therefore covers systems comprising a large genus of genetically modified ubiquitin for labeling a large genus of analytes characterized by substantial variability.
Regarding the predictability or unpredictability in the art, the applicant has attested that the SidE ADP Ribosyltransferase (ART) domain transfers an ADP ribose to an internal Arg residue on ubiquitin (Arg42). See para. [0125] of the applicant’s specification. The applicant has not provided evidence that the ART domain can transfer an ADP ribose to a genetically modified ubiquitin lacking Arg42. The large genus of genetically modified ubiquitin includes proteins that lack Arg42 and proteins that have minimal resemblance to wild-type ubiquitin.
The specification’s actual reduction to practice is limited to only one genetically modified ubiquitin. See under “Example 1” of the applicant’s specification. The reduction to practice of only ubiquitin with the C-terminal diglycine mutated to dialanine. The disclosure of one genetically modified ubiquitin is insufficient to show the possession of the entire genus of genetically modified ubiquitin.
Furthermore, there is also no disclosure of the partial structure common to the members of the genus of genetically modified ubiquitin that would correlate with function (in this case, the claimed function of being a substrate for the ART domain). The claim is not limited to genetically modified ubiquitin with the common structure necessary to act as a substrate for the ART domain.
The importance of structure/function correlations was recently highlighted by the courts (Abbvie Deutschland v. Janssen Biotech and Centocor Biologics, App. No. 2013-1338, -1346 (Fed. Cir., July 1, 2014)). The Abbvie case involved antibodies and written description. The court stated: “We have held that “a sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Id. at 1350 (quoting Eli Lilly, 119 F.3d at 1568– 69)”. The courts then further stated: “With the written description of a genus, however, merely drawing a fence around a perceived genus is not a description of the genus. One needs to show that one has truly invented the genus, i.e., that one has conceived and described sufficient representative species encompassing the breadth of the genus. Otherwise, one has only a research plan, leaving it to others to explore the unknown contours of the claimed genus.” (emphasis added) and then state: " Functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support, especially in technology fields that are highly unpredictable, where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus. Ariad, 598 F.3d at 1351 (“[T]he level of detail required to satisfy the written description requirement varies depending on the nature and scope of the claims and on the complexity and predictability of the relevant technology.”); see also Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1352 (Fed. Cir. 2011) (noting the technical challenges in developing fully human antibodies of a known human protein). It is true that functionally defined claims can meet the written description requirement if a reasonable structure-function correlation is established, whether by the inventor as described in the specification or known in the art at the time of the filing date. Enzo Biochem, Inc. v. Gen-Probe Inc., 323 F.3d 956, 964 (Fed. Cir. 2002).
There is no partial structure or other identifying characteristics disclosed, common to the members of the genus of genetically modified ubiquitin capable of acting as a substrate for the ART domain, that would allow one skilled in the art to envision that the applicant has truly invented the genus, i.e., that one has conceived and described sufficient representative species encompassing the breadth of the genus.
For all of these reasons, the specification does not demonstrate possession of the entire genus of genetically modified ubiquitin having the claimed functional characteristics of acting as a substrate for the ART domain.
Additionally, claims 10 is directed to a system for proximity-based labeling of a biomolecule comprising a biomolecule derivative. The claim imposes no restriction on the size of the biomolecule derivative.
The scope of the claims therefore covers systems comprising a large genus of biomolecule derivatives characterized by substantial variability. “Biomolecule” is a generic term with an extremely large number of representative species. In para. [0029] of the applicant’s specification, the applicant discloses, “The term "biomolecule" as used herein refers to, but is not limited to, proteins, enzymes, antibodies, DNA, siRNA, and small molecules. "Small molecules" as used herein can refer to chemicals, compounds, drugs, and the like”.
The specification’s actual reduction to practice is limited to two biomolecule derivatives. See under “Fig. 4A” and “Fig. 4B” of the applicant’s drawings filed 03/02/2022. The specification provides no disclosure of specific species of biomolecule derivatives other than two small molecule derivatives. However, derivatives of proteins, enzymes, antibodies, and DNA are encompassed in the large genus of biomolecule derivatives and no disclosure of such species is found in the applicant’s specification. Also, the only guidance related to creating derivatives of proteins, enzymes, antibodies, and DNA for the claimed invention given in the applicant’s specification refers merely to “conventional” methods without specifics. See para. [0079] of the applicant’s specification.
The disclosure of general methods that might be used to make biomolecule derivatives is insufficient to describe the claimed genus of biomolecule derivatives. The Federal Circuit addressed an analogous situation in University of Rochester v. G.D. Searle & Co., Inc., 358 F.3d 916, 927 (Fed. Cir. 2004), finding that disclosure of “assays for screening compounds, including peptides, polynucleotides, and small organic molecules to identify those that inhibit the expression or activity of the PGHS-2 gene product,” did not satisfy the written description requirement for claims requiring administration of a “compound that selectively inhibits PGHS-2.” Rochester, 119 F.3d at 918, 927; see also Ariad Pharmaceuticals, Inc., v. Eli Lilly and Company, 598 F.3d 1336, 1344 (Fed. Cir. 2010) (recognizing distinction between requirements for written description and enablement).
Furthermore, there is also no disclosure of any partial structure common to the members of the genus of biomolecule derivatives that would correlate with function (in this case, the claimed function of compatibility with the system for proximity-based labeling).
The importance of structure/function correlations was recently highlighted by the courts (Abbvie Deutschland v. Janssen Biotech and Centocor Biologics, App. No. 2013-1338, -1346 (Fed. Cir., July 1, 2014)). The Abbvie case involved antibodies and written description. The court stated: “We have held that “a sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Id. at 1350 (quoting Eli Lilly, 119 F.3d at 1568– 69).”. The courts then further stated: “With the written description of a genus, however, merely drawing a fence around a perceived genus is not a description of the genus. One needs to show that one has truly invented the genus, i.e., that one has conceived and described sufficient representative species encompassing the breadth of the genus. Otherwise, one has only a research plan, leaving it to others to explore the unknown contours of the claimed genus.” (emphasis added) and then state: " Functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support, especially in technology fields that are highly unpredictable, where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus. Ariad, 598 F.3d at 1351 (“[T]he level of detail required to satisfy the written description requirement varies depending on the nature and scope of the claims and on the complexity and predictability of the relevant technology.”); see also Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1352 (Fed. Cir. 2011) (noting the technical challenges in developing fully human antibodies of a known human protein). It is true that functionally defined claims can meet the written description requirement if a reasonable structure-function correlation is established, whether by the inventor as described in the specification or known in the art at the time of the filing date. Enzo Biochem, Inc. v. Gen-Probe Inc., 323 F.3d 956, 964 (Fed. Cir. 2002).
There is no partial structure or other identifying characteristics disclosed, common to the members of the genus of biomolecule derivatives, that would allow one skilled in the art to envision that the applicant has truly invented the genus, i.e., that one has conceived and described sufficient representative species encompassing the breadth of the genus.
For all of these reasons, the specification does not demonstrate possession of the entire genus of biomolecule derivatives having the claimed functional characteristics of compatibility with a system for proximity-based labeling of a biomolecule.
Claim 17 is directed to a method for detecting an interaction between a biomolecule or a protein of interest and a target protein. The claim imposes no restriction on the size or structure of the biomolecule or protein of interest.
The scope of the claims therefore covers systems comprising a large genus of biomolecules and proteins of interest characterized by substantial variability. “Biomolecule” is a generic term with an extremely large number of representative species. In para. [0029] of the applicant’s specification, the applicant discloses, “The term "biomolecule" as used herein refers to, but is not limited to, proteins, enzymes, antibodies, DNA, siRNA, and small molecules. "Small molecules" as used herein can refer to chemicals, compounds, drugs, and the like”.
The specification’s actual reduction to practice is limited to two biomolecules. See under “Fig. 4A” and “Fig. 4B” of the applicant’s drawings filed 03/02/2022. The specification provides no disclosure of specific species of biomolecule derivatives other than two small molecule derivatives. However, proteins, enzymes, antibodies, and DNA are encompassed in the large genus of biomolecules or proteins of interest and no disclosure of such species is found in the applicant’s specification. Also, the only guidance related to creating proteins, enzymes, antibodies, and DNA for the claimed invention given in the applicant’s specification refers merely to “conventional” methods without specifics. See para. [0079] of the applicant’s specification.
The disclosure of general methods that might be used to make biomolecules or proteins of interest is insufficient to describe the claimed genus of biomolecules or proteins of interest. The Federal Circuit addressed an analogous situation in University of Rochester v. G.D. Searle & Co., Inc., 358 F.3d 916, 927 (Fed. Cir. 2004), finding that disclosure of “assays for screening compounds, including peptides, polynucleotides, and small organic molecules to identify those that inhibit the expression or activity of the PGHS-2 gene product,” did not satisfy the written description requirement for claims requiring administration of a “compound that selectively inhibits PGHS-2.” Rochester, 119 F.3d at 918, 927; see also Ariad Pharmaceuticals, Inc., v. Eli Lilly and Company, 598 F.3d 1336, 1344 (Fed. Cir. 2010) (recognizing distinction between requirements for written description and enablement).
Furthermore, there is also no disclosure of any partial structure common to the members of the genus of biomolecules or proteins of interest that would correlate with function (in this case, the claimed function of compatibility with the system for proximity-based labeling).
The importance of structure/function correlations was recently highlighted by the courts (Abbvie Deutschland v. Janssen Biotech and Centocor Biologics, App. No. 2013-1338, -1346 (Fed. Cir., July 1, 2014)). The Abbvie case involved antibodies and written description. The court stated: “We have held that “a sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Id. at 1350 (quoting Eli Lilly, 119 F.3d at 1568– 69).”. The courts then further stated: “With the written description of a genus, however, merely drawing a fence around a perceived genus is not a description of the genus. One needs to show that one has truly invented the genus, i.e., that one has conceived and described sufficient representative species encompassing the breadth of the genus. Otherwise, one has only a research plan, leaving it to others to explore the unknown contours of the claimed genus.” (emphasis added) and then state: " Functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support, especially in technology fields that are highly unpredictable, where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus. Ariad, 598 F.3d at 1351 (“[T]he level of detail required to satisfy the written description requirement varies depending on the nature and scope of the claims and on the complexity and predictability of the relevant technology.”); see also Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1352 (Fed. Cir. 2011) (noting the technical challenges in developing fully human antibodies of a known human protein). It is true that functionally defined claims can meet the written description requirement if a reasonable structure-function correlation is established, whether by the inventor as described in the specification or known in the art at the time of the filing date. Enzo Biochem, Inc. v. Gen-Probe Inc., 323 F.3d 956, 964 (Fed. Cir. 2002).
There is no partial structure or other identifying characteristics disclosed, common to the members of the genus of biomolecule derivatives, that would allow one skilled in the art to envision that the applicant has truly invented the genus, i.e., that one has conceived and described sufficient representative species encompassing the breadth of the genus.
For all of these reasons, the specification does not demonstrate possession of the entire genus of biomolecules or proteins of interest having the claimed functional characteristics of compatibility with a system for proximity-based labeling of a biomolecule.
Claims 15-16, 18, and 21-29 are also rejected under 35 U.S.C. 112(a) because they depend on the rejected independent claims 10 and 17.
Declaration under 37 C.F.R. § 1.132
The declaration under 37 C.F.R. § 1.132 filed 04/08/2026, i.e., the Tagliabracci declaration, has been considered. However, the 35 U.S.C. 103 rejections that the declaration contests have been withdrawn, necessitated by amendments filed 04/08/2026.
Response to Arguments
The arguments filed 04/08/2026 have been fully considered. However, the 35 U.S.C. 103 rejections that the arguments contest have been withdrawn, necessitated by amendments filed 04/08/2026.
Conclusion
Claims 10, 15-18, and 21-29 are rejected on the grounds of 35 U.S.C. 112(a), but the claims are free of the prior art.
The prior art of record does not teach or make obvious independent claim 10:
“A system for proximity-based labeling of a biomolecule, the system comprising:
(a) at least one construct comprising at least one genetically modified ubiquitin (Ub), a self-labeling protein tag, and a linker;
(b) a biomolecule derivative; and
(c) an active ADP-ribosyltransferase (ART) domain of a (i) SidE-ligase protein, (ii) an ortholog of SidE-ligase protein, or (iii) a paralog of a SidE-ligase protein, and
(d) an active phosphodiesterase (PDE) domain of (i) a SidE-ligase protein, (ii) an ortholog of SidE-ligase protein, or (iii) a paralog of a SidE-ligase protein, the active phosphodiesterase (PDE) domain and the active ADP-ribosyltransferase (ART) domains are provided in separate polypeptides”.
The closest prior art is Hill (Direct Proximity Tagging of Small Molecule Protein Targets Using an Engineered NEDD8 Ligase, J. Am. Chem. Soc. 2016, 138, 13123−13126 , published 2016-09-14, cited in PTO-892 dated 03/26/2025).
Hill teaches a system for proximity-based labeling of a biomolecule comprising a ubiquitin homolog, a self-labeling protein tag, a linker, a biomolecule derivative, and a ubiquitin homolog-ligating enzyme, as in claim 10 (see, e.g., ubiquitin homolog, self-labeling protein tag, and ubiquitin homolog-ligating enzyme - under “Figure 1”; biotin-acceptor peptide – under “Figure S2”; linker – under “Figure S4”).
However, Hill fails to teach the ADP-ribosyltransferase (ART) domain of a SidE-ligase protein and the active phosphodiesterase (PDE) domain of a SidE-ligase protein, as in claim 10.
The prior art of record does not teach or make obvious independent claim 17:
“A method for detecting an interaction between a biomolecule or a protein of interest and a target protein, the method comprising:
(a) contacting a sample comprising the target protein with a construct comprising an ADP-ribosylated ubiquitin (Ub) and (i) a self-labeling protein tag conjugated to the biomolecule or (ii) the protein of interest, for a period of time sufficient for the biomolecule or the protein of interest to associate with the target protein present in the sample;
(b) contacting the sample with a PDE domain of (i) a SidE-ligase protein, (ii) an ortholog of SidE-ligase protein, or (iii) a paralog of a SidE-ligase protein, wherein the PDE domain covalently links the ADP-ribosylated Ub to the target protein in the sample via a phosphoribose linkage; and
(c)detecting whether the target protein is bound to the construct, indicating that the interaction between the biomolecule or protein of interest and the target protein is present in the sample”.
The closest prior art is O'Connor (Ubiquitin-Activated Interaction Traps (UBAITs): Tools for Capturing Protein-Protein Interactions, Springer Protocols, published 2018-09-22, cited in PTO-892 dated 03/26/2025). O’Connor teaches detecting a protein interaction with a target biomolecule by contacting a sample with a biomolecule sensor comprising a ubiquitin, a linker, an epitope tag, a target protein, and a ubiquitin-conjugating enzyme, wherein detection occurs when the target biomolecule is bound to the target protein, indicating protein interaction with a target biomolecule is present in the sample, as in claim 17 (see, e.g., under “Fig. 1A”).
However, O’Connor fails to teach contacting the sample with the PDE domain of the SidE-ligase protein, as in claim 17.
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/MICHAEL CAMERON SVEIVEN/Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
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