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 .
Response to Amendment
Applicant’s response filed 04/30/2026 is acknowledged. Claims 1, 8, 10-16, 18-20 are amended, claim 21 is newly canceled and claims 26-29 are new.
Claims 1-20 and 26-29 are under examination.
Nucleotide and/or Amino Acid Sequence Disclosures
The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) added to the specification in the amendment filed 04/30/2026 is acknowledged.
Objections/Rejections Withdrawn
Any previous objections or rejections of claim 21 are hereby withdrawn in response to Applicant’s cancelation of that claim.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Specification
The objection to the disclosure because it contains an embedded hyperlink and/or other form of browser-executable code at p. 17, line 22 is withdrawn in response to Applicant’s amendment of the specification filed 04/30/2026.
Claim Objections
The objection to claims 1-20 for minor informalities is withdrawn in response to Applicant’s amendment filed 04/30/2026 in which the text is written plainly and legibly as set forth in 37 CFR 1.52(a) and (b). Further, claim 16 has been amended to recite “or”, thereby improving the grammar.
Claim Rejections - 35 USC § 112(b)
The rejection of claims 1-20 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is withdrawn in response to Applicant’s amendment. Specifically, claims 1, 8, 10-15 and 20 have been amended to remove the exemplary language. In addition, claim 8 has been amended to delete the trademark/trade name “nanobody”. Further, the issue regarding insufficient antecedent basis in claim 9 is overcome in response to Applicant’s amendment of that claim to depend from claim 6. Similarly, the issue regarding insufficient antecedent basis of claims 10, 18 and 19 is overcome in response to Applicant’s amendment of these claims to depend from claim 4
Claim Rejections - 35 USC § 112 – Scope of Enablement
The rejection of claims 1-20 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph for scope of enablement is withdrawn in response to Applicant’s amendment. Applicant has amended the claims to address the issue raises with regard to combinations in which the E3 ligases and membrane bound proteins need only share 60% sequence identity with the wild-type protein (see p. 43, lines 3-5 and p. 49, lines 11-20). Specifically, the amended claims require that the transmembrane E3 and membrane bound proteins are both wild-type.
Rejections Maintained
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.
Written Description
The rejection of claims 1-20 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 is maintained for reasons of record and the following. In addition, new claims 26-29 are hereby included in this rejection.
Response to Arguments
Applicant argues at p. 10 of the Remarks filed 04/30/2026 that the amendment to claim 1 specifying that the heterobifunctional molecule is a bi-specific antibody adds structural features. Further, Applicant asserts that the bi-specific antibodies used in the method as claimed can be produced using routine procedures that would be known to the skilled person, citing the instant specification at pages 55, lines 26 - 35, page 57, lines 14-21.
These arguments have been fully considered, but are not found persuasive. First, the claims have been amended to recite that the heterobifunctional molecule is a bi-specific antibody, but this still represents a genus of molecules. To support this genus, the instant specification discloses several working examples that employs the bi-VHH, VHH Alpha - (G4S)3 - VHH E6, in which the first binding domain is an anti-Alpha VHH and the second binding domain is an anti-E6 VHH (see pages 71-72). The examples show that the Alpha and E6 epitope targets were recombinantly fused to a transmembrane E3 ubiquitin ligase and a transmembrane protein, respectively (e.g. see Example 1, pages 70-72). Therefore, based on the content of the disclosure, the VHH Alpha - (G4S)3 - VHH E6 bi-VHH binds non-native epitope tags on the membrane-bound proteins (targets) and not the targets themselves. Thus, the claimed genus of bispecific antibodies that bind an extracellular portion of a transmembrane E3 ubiquitin ligase and an extracellular portion of a membrane-bound protein do not have sufficient written description. Further, none of the claims at issue recite any structural limitations specific to the bi-specific antibodies, such as specific CDRs.
It is noted that the applicant has claimed a genus of bispecific antibodies that bind to a transmembrane E3 ubiquitin ligase and to a transmembrane protein to be used in a screening assay for targeted protein degradation. However, claim 1 does not indicate any specific structure for this genus, nor does it indicate any specific species of transmembrane E3 ubiquitin ligase or transmembrane protein that the bispecific antibody would bind nor where upon them it would bind. Only claims 6 and 9 recites that the first and/or second tag may be either an Alpha or an E6 tag. Nevertheless, knowledge of a given antigen (e.g., a transmembrane E3 ubiquitin ligase, an epitope tag) provides no information concerning the sequence/structure of antibodies that bind the given antigen. 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. Townsend et al. (Frontiers in Immunology, 2016; 7: 388) teach “[v]ariability in the antigen binding site is achieved by V(D)J recombination via heavy and light chain pairing”, with the “most diverse” regions being the 6 CDR regions in the heavy and light chains.
While the heavy chain is the most diverse, light chains are also important for binding specificity of antibodies, swapping light chains can “change the antigen specificity of the antibody” (see paragraph bridging pages 1-2). In addition, the light chain repertoire is extremely diverse, being encoded by kappa and lambda gene segments, each with different V and J genes (see Townsend, p. 2, left column, 1st two paragraphs; p. 4, right column, 1st paragraph). See also Janeway et al. (Chapter 4-The generation of diversity in immunoglobulins in Immunobiology: The Immune system in health and disease, 5th edition, New York, Garland Science, 2001), which teaches that the “antibody repertoire in humans is at least 1011”, with a large degree of diversity in both heavy and light chains (see 1st paragraph). Furthermore, the diversity of the immunoglobulin repertoire is mediated in part by different combinations of heavy and light chain V regions that pair to form a unique antibody binding site. See, for example, Rabia et al. (Biochem. Engin. J. 137, 365-374, 2018), which teaches that “the maximal chemical diversity of antibody CDRs is unimaginably large…[and] it is extremely challenging to define the sequence determinant of antibody specificity” (see p. 368 left column, 4th paragraph).
As such, it is not possible to predict the sequence/structure of an antibody that binds a given antigen. It is noted that the specification does not appear to discuss any specific heterobifunctional molecules that bind to a transmembrane E3 ubiquitin ligase and to a membrane-bound protein that are found in the prior art or that were synthesized by applicant in the instant specification. Rather the specification discloses the bi-specific antibody, VHH Alpha - (G4S)3 - VHH E6, that binds to epitope tags that have been recombinantly fused to extracellular portions of the transmembrane E3 ubiquitin ligase and the membrane-bound protein, but do not bind to the targets themselves. Such a disclosure does not serve to provide a written description of a heterobifunctional molecule that binds to a transmembrane E3 ubiquitin ligase and to a membrane-bound protein as it does not identify any specific structural features or combination of features which give rise to the function of bispecific binding to a transmembrane E3 ubiquitin ligase and a transmembrane domain. Further, there does not appear to be any reasonable shared structure present in the genus of recited bi-specific antibodies which gives rise to their functional activity. As such, the instant specification appears to disclose applicant’s wish for heterobifunctional molecules that bind to a transmembrane E3 ubiquitin ligase and to a transmembrane protein without informing artisans what such heterobifunctional molecules actually are.
Ultimately, identifying a bispecific antibody simply on the basis of what it binds rather than by identifying the sequence/structure of the antibody in question is generally insufficient to provide written description of the antibody in question. Therefore, in view of the generic nature of the instant specification, artisans would reasonably conclude that applicant was not in possession of the entire genus of heterobifunctional molecules that bind to the extracellular portions of a transmembrane E3 ubiquitin ligase and a membrane-bound protein at the time the instant application was filed.
Second, it is noted regarding bi-specific antibodies, the skilled artisan cannot envision the detailed chemical structure of the genus of bi-specific antibodies, 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, citing Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. The 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). 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.
The rejection of claims 1-3, 8, 11, 15-17 and 20 under 35 U.S.C. 103 as being unpatentable over Throsby et al. (WO2017069628—on IDS filed 11/21/2022) in view of Riching et al. (ACS Chem Biol. 2018; 13: 2758-2770) and Bondeson et al. (Cell Chemical Biology, 2018, 25, 78-87—on IDS 11/21/2022) is maintained for reasons of record and the following. In addition, new claim 26 is hereby included in this rejection. Specifically, Throsby et al. teach measuring membrane bound protein via immunofluorescence (see p. 116, lines 5-16).
Response to Arguments
Applicant argues at pages 11-12 in the Remarks filed 04/30/2026 that the primary reference by Throsby does not teach or suggest a combination that results in lysosomal degradation as required in amended claim 1, but rather, the binding arm in the method blocks ligand binding (e.g., “‘Ligand blocking capacity of the anti-EGFR Fab arm in PB10651’”). Further, Applicant argues that the person having ordinary skill in the art would not combine the references by Riching et al. and Bondeson et al., asserting that there is no motivation to combine because Throsby is directed to extracellular receptor blocking while the secondary references concern intracellular degradation.
This argument has been fully considered, but is not found persuasive. Instant claim 1 is drawn to the steps of providing a cell expressing both a transmembrane E3 ligase and a membrane-bound protein at the cell surface, exposing the cell to a heterobifunctional molecule with two binding domains, one for the E3 ligase and one for the membrane-bound protein and measuring whether the membrane-bound protein’s surface level decreases after exposure. The amendment to claim 1 recites that the combination is effective when the E3 ubiquitin ligase is capable of decreasing the surface level of membrane-bound protein upon simultaneous binding to a heterobifunctional molecule by ubiquitination of the membrane-bound protein for subsequent internalization and lysosomal degradation, which describes the process of ubiquitination.
The amendment reciting the modification of the ligase and membrane-bound proteins to comprise a non-native epitope tag is optional, and therefore not required. As noted by Applicant, the primary reference by Throsby et al. is missing the teaching of ubiquitination; rather, they teach the binding arm in the method blocks ligand binding. Applicant asserts further that one having ordinary skill in the art would not combine Throsby et al. with the secondary references by Richting et al. and Bondeson et al. because they concern different methodologies, namely extracellular receptor blocking vs. ubiquitination. The examiner relied upon the reference by Riching et al. which teaches an “innovative, modular live cell platform” to screen proteolysis-targeting chimeras (PROTACs), which are bifunctional molecules, for their ability to “[target] proteins for degradation through recruitment to E3 ligases”, namely, VHL- and CRBN (see abstract; p. 2758, left column; p. 2759, paragraph bridging left and right columns). In addition, the reference by Bondeson et al. was relied upon for its teaching that there is “a strong correlation between [target] proteins that stably [interact] with VHL [an E3 ubiquitin ligase] and those that are degraded” and that “degradation potency” of a given protein depends on the ability of said protein to “form a stable ternary complex with the PROTAC [e.g., a bispecific antibody] and the recruited E3 ubiquitin ligase” (see p. 82, left column; p. 83, right column, last paragraph). The PROTAC technology described in the secondary references is conceptually similar to the screening technology taught by Throsby and colleagues.
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to modify the in vitro cell culture system comprising a cell that expresses the ZNRF/EGFR or RNF43/EGFR combination as taught in Throsby et al. in order to determine the effectiveness of membrane protein degradation in response to bispecific antibody binding because Riching et al. teach that bispecific antibodies such as PROTACs “induce [target protein] degradation by simultaneously binding the target protein and the E3 ligase complex proteins, bringing the target protein into proximity for ubiquitination and targeting it for degradation through the UPS [ubiquitin proteasomal system]” (see p. 2758, 1st paragraph). In addition, the person having ordinary skill in the art would have recognized that UPS-based target protein degradation is correlated with a strong interaction (i.e., effective combination) between the E3 ligase and the target protein (see Bondeson and colleagues).
Conclusion
No claim is allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/CHRISTINA M BORGEEST/Primary Examiner, Art Unit 1675
Prosecution Insights