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 .
Priority
The instant application, filed 05/24/2023, claims domestic benefit to US provision application 63/323,474, filed 03/24/2022.
Claim Status
Claims 1-16 are pending in the instant application and are examined on the merits herein.
Election/Restrictions
Applicant’s election without traverse of the following species in the reply filed on 11/24/2025 is acknowledged.
Species 1: SEQ ID NOs: 18, 41, and 60 as CDRs 1-3, respectively.
Species 2, 3, and 4: SEQ ID NO: 120 (nanobody 3SPC11)
Rejoinder
Claims readable on the elected species are free from prior art. Pursuant to the procedures set forth in MPEP § 821.04(a), the restriction requirement among species, as set forth in the Office action mailed on 10/21/2025, is hereby withdrawn and species as set forth in claims 1-4 are hereby rejoined and fully examined for patentability under 37 CFR 1.104. In view of the withdrawal of the restriction requirement, applicant(s) are advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application. Once the restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
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.
Specification
The disclosure is objected to because of the following informalities: “aspect io14” (¶ [0060], line 1) is unclear and should be defined or edited as necessary.
Appropriate correction is required.
The use of the terms “Octet” (¶ [0025], line 2), “Pierce” (¶ [0063, line 6; ¶ [0066], line 1), “Vivaspin” (¶ [0066], line 4), which are trade names or marks used in commerce, have been noted in this application. Each term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claims 7 is objected to because of the following informalities: “at least pharmaceutically acceptable excipient” should read “at least one pharmaceutically acceptable excipient.” 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 2-4 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.
Regarding claim 2, base claim 1 recites a nanobody comprising CDRs of “any one” of the nanobody sequences set forth in SEQ ID NOs: 72-134. The instant claims recites the protein of claim 1 “comprising CDR sequences (i)-(viii).” As currently written, this introduces ambiguity in claim interpretation as it is unclear if the claim is drawn to include all of the listed sequences (i.e. the claims read on a species of protein comprising 8 different VHH sequences) or if instead if the species should correspond to the single selected CDR set sequences of the base claim. Examiner recommends amending the claim to recite “comprising the CDR sequences selected from one of the following” to prevent ambiguity, and for examination examiner has interpreted the claim based on this recommendation.
Regarding claim 3, base claim 1 recites “any one” of CDR sets from the nanobody sequences provided as stated above. The instant claim recites the protein of claim 1, comprising “one or more” of the nanobody sequences SEQ ID NOs: 72-134. The base claims is drawn to a singular species of CDR sequences, but the recited nanobody sequences in claim 3 have several different CDR sequences (i.e. species (i)-(viii)) introducing ambiguity into the claim. Examiner recommends amending the claim to recite “The protein of claim 1, wherein the nanobody comprises an amino acid sequence set forth in SEQ ID NOs: 72-134” if the intention is to claim a full sequence that corresponds a singular set of CDRs as recited in the base claim (examiner’s interpretation for examination purposes) or reciting a “further comprising” clause if the goal is to introduce additional nanobody species to the protein of claim 1 (i.e. multivalent nanobody). If applicant’s intention is both, these concepts should be presented in separate claims to avoid ambiguity.
Regarding claim 4, it is unclear if the claim is limiting all species within the protein (i.e. narrowing the range of potential sequences as recited in claim 3) or if the claim is reciting the protein would further comprise the sequences listed. Examiner recommends amending the claim to recite “The protein of claim 3, wherein the one or more human-calreticulin binding nanobody amino acid sequences are selected from the following amino acid sequences [SEQ ID NOs listed]” if the aim is to limit the full set of species (examiner’s interpretation for examination purposes), or to recite a “further comprising” clause if the goal is to incorporate one of the instantly listed species in additional to one of the species as listed in the full set of the base claim
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-3, 5, and 7 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO 2021/095031 A2 (herein WO’031) as evidenced by Rowe (Handbook of Pharmaceutical Excipients. 6th ed. London: Pharmaceutical Press, 2009).
Regarding claims 1-3 and 5, WO’031 teaches an anti-NPC1 single domain antibody (SEQ ID NO:551), constructed into a VHH library (pg. 82, lines 21-22), identical to instant SEQ ID NO:102, and comprising identical CDRs corresponding to instant SEQ ID NOs: 11, 35, and 57 (see annotated alignment below; CDRs highlighted).
Instant SEQ ID NO:102 (Qy) aligned with WO’031 SEQ ID NO:551 (Db):
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255
628
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When structures in a reference are identical to that of the claims, the claimed properties or functions are presumed to be inherent (See MPEP 2112.01). Therefore, though not explicitly recited to bind to human calreticulin (i.e. function), the identical nanobody (i.e. structure) as taught by WO’031 would inherently perform the same function and therefore anticipates the instant claims.
Regarding claim 7, WO’031 teaches the protein of claim 2 as discussed above. WO’031 further teaches generated nanobodies were suspended in PBS for larval feeding bioassays (pg. 84, ¶ 3). A skilled artisan would recognize the base components for PBS (sodium phosphate/potassium phosphate and water) are considered pharmaceutically acceptable excipients as evidenced by Rowe (pg. 656-660), and therefore anticipates “at least one pharmaceutically acceptable excipient” as recited in the instant claim.
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.
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over WO’031 as applied to claim 2 above, and further in view of De Greve (Curr Opin Biotechnol. 2020;61:96-101).
WO’031 teaches claim 2 as discussed above.
WO’031 does not teach nanobody Fc fusion.
De Greve teaches fusing Fc domains to VHH of interest increases half-life and effector functions including ADCC (pg. 97, left column, ¶ 2; pg. 98, left column, ¶ 2).
Therefore, It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to combine a known nanobody as taught by WO’031 with an Fc domain because De Greve teaches this improves longevity and therapeutic effects of fused nanobodies.
Claims 8-16 are rejected under 35 U.S.C. 103 as being unpatentable over WO’031 as applied to claim 2 above, and further in view of Rashidian (Immunooncol Technol. 2020;7:2-14), CN 111289749 A (herein Jiang), and Suigara (Molecules. 2014;19(2):2135-2165).
WO’031 teaches claim 2 as discussed above. WO’031 further teaches nanobodies, including an NPC1 nanobody identical to sequences recited in the instant claims, can be conjugated to various detectable or reporter moieties including but not limited to radioactive isotopes, with practical examples of live imaging in larvae fed fluorescently-labeled nanobodies (pg 85, ¶ 2).
WO’031 does not explicitly teach conjugation to a radionuclide nor methods of radionuclide-protein fusion.
Rashidian teaches nanobody properties including small size, stability, specificity, and ease of manufacture are ideal for use as imaging agents in the laboratory and the clinic (abstract). Non-invasive imaging methods using radioisotope labelled nanobodies to visualize and track location, movement and quantity of the target molecule through current imaging techniques (i.e. PET or “immunoPET”) allows global insight of specific markers without the need for biopsies (i.e. during cancer diagnostics) (pg. 2-3 spanning ¶; pg. 3, column spanning ¶). Rashidian further teaches several nanobodies (targeting HER2) developed for ‘same-day imaging’ using different labeling strategies including radionuclides 131I, 225Ac, and 177Lu (pg. 5, left column, ¶ 3; references 103 and 104). Rashidian briefly discusses generation radionuclide tagged VHH involves installation of radiometal chelators or click handles (Figure 2 legend).
Jiang teaches NPC1 abundance is correlated to poor prognosis in patients with liver cancer and teaches NPC1 detection as a means of diagnosing cancer, predicting cancer prognosis, or as a therapeutic target (abstract).
Sugiura teaches that alpha and beta particle emitting radionuclides (e.g. 225Ac, 90Y, 131I, and 177Lu) can used for imaging and radiotherapy. Suigara teaches there are various strategies available to incorporate a radionuclide into a protein and that the choice of technique depends primarily on the radionuclide used. Sugiura teaches radioactive metals (e.g. 90Y and 225Ac) are labeled via complexation with a chelating agent (pg. 2151, last ¶). Sugiura further teaches macrocyclic chelators, such as DOTA and its derivatives, are useful in molecular imaging because they form stable complexes with divalent and trivalent metals and possess greater in vivo stability than alternative acyclic chelators (pg. 2151, last ¶).
One of ordinary skill would recognize that for biomarker detection in larger organisms (i.e. mice or humans), fluorescent labels would be insufficient for internal detection. Therefore, it would have been obvious to one of ordinary skill prior to the effective filing date of the claimed invention to substitute a NPC1 nanobody (or pharmaceutical composition thereof) conjugated fluorescent tag as taught by WO’031 with a known clinically suitable radionuclide (e.g. 131I, 225Ac, and 177Lu) because Rashidian teaches these as compatible with current non-invasive imaging technologies used in preclinical and human models and an artisan would be motivated to do so because Jiang teaches NPC1 expression as a prognostic cancer biomarker. Furthermore, it would have been obvious to one of ordinary skill in the art to combine a known nanobody as taught by WO’031 with a metal chelating agent as taught by Rashidian because Sugiura teaches radioactive metals require complexing with a chelating agent, and it would be obvious to a skilled artisan to use DOTA or derivatives thereof as Sugiura further teaches they possess greater stability in vivo.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
US 18/862,655
Claims 1-3 and 5-16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 and 5-17 of copending Application No. 18/862,655 (herein US655). Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding claims 1-3, Claim 1 of US655 claims a huGRP78-binding nanobody comprising CDR sequences that are identical to CDRs recited in instant claims 1-2 (SEQ ID NOs: 15, 31, and 51 are identical to instant SEQ ID NOs: 11, 35, and 57, respectively). Claim 2 of US655 (dependent on claim 1) claims an identical full nanobody sequence (SEQ ID NO:79 is identical to instant SEQ ID NO:110). As discussed above. With identical structures (e.g. nanobody sequences), claimed properties or functions are presumed to be inherent (See MPEP 2112.01). Therefore, despite difference in claimed properties (i.e. binding affinities) between applications, identical nanobodies are considered patentably indistinct.
Regarding claim 5, claim 5 of US655 (dependent on claim 1) claims the protein is a single VHH domain.
Regarding claim 6, claim 6 of US655 (dependent on claim 1) claims the protein is an Fc fusion protein.
Regarding claim 7, claim 7 of US655 claims a pharmaceutical composition comprising the protein of claim 1 and a pharmaceutically acceptable excipient.
Regarding claim 8, claim 8 of US655 claims a radiopharmaceutical composition comprising the protein of claim 1 linked to radionuclide.
Regarding claim 9, claim 9 of US655 (dependent on claim 8) claims the composition further comprises a pharmaceutically acceptable excipient.
Regarding claims 10-11, claims 10-11 of US655 (dependent on claim 9) claims the radionuclide is an alpha (claim 10) or beta (claim 11) particle emitter.
Regarding claims 12-13, claims 12-13 of US655 (dependent on claim 9) claim identical radionuclide species, respectively.
Regarding claim 14, claim 14 of US655 (dependent on claim 1) claim a composition comprising the protein of claim 1 chemically conjugated to a chelator.
Regarding claim 15, claim 15 of US655 (dependent on claim 14) further claims the chelator comprises DOTA or a DOTA derivative.
Regarding claim 16, claims 16-17 of US655 (dependent on claims 14 and 15, respectively) claims the compositions further comprise a radionuclide chelated by the chelator.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Allowable Subject Matter
CDR sets recited in claim 2(i)-(v) and (vii)-(viii) and corresponding nanobody sequences are free from prior art.
Claim 4 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
No claims are currently allowed
Any inquiry concerning this communication or earlier communications from the examiner should be directed to HANNAH SUNSHINE whose telephone number is (571)270-7417. The examiner can normally be reached M-Th & Second Friday 8:30am-5pm EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Joanne Hama can be reached at (571) 272-2911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/HANNAH SUNSHINE/Examiner, Art Unit 1647 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647