Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Status of the Claims
1. Claims 1-23 are the original claims filed on 8/24/2022. In the Preliminary Amendment of 8/24/2022, claims 1-16, 18-19 and 21-22 are amended and claims 17, 20, and 23 are canceled. In the Response of 8/4/2026, Claims 1, 3, 7-11 and 16 are amended and claims 4-6 and 12 are canceled.
Claims 1-3, 7-11, 13-16, 18-19 and 21-22 are all the claims.
Claims 21-22 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 11/20/2025.
Claims 1-3, 7-11, 13-16, and 18-19 are the claims under examination.
Applicants amendment of the claims raises new grounds for rejection. The Office Action is final.
Priority
2. USAN 17/801,921, filed 08/24/2022, is a National Stage entry of PCT/EP2021/ 054339, International Filing Date: 02/22/2021, PCT/EP2021/054339 Claims Priority from Provisional Application 62/981,200, filed 02/25/2020, and claims foreign priority to EP 20212466.5, filed 12/08/2020, and claims foreign priority to EP 20165463.9, filed 03/25/2020.
Information Disclosure Statement
3. As of 9/18/2026, a total of two (2) IDS are filed: 8/24/2022; and 12/6/2022. The corresponding initialed and dated 1449 form is considered and of record. The submissions are in compliance with the provisions of 37 CFR 1.97.
Withdrawal of Objections
Drawings
4. The amendment to the drawing sheet for Figure 2A-2C addresses the objection.
The amendment to the drawing sheet for Figure 15 addresses the objection.
Specification
5. The amendment of the abstract of the disclosure addresses the objection.
6. The objections to the specification are withdrawn. Both clean substitute and marked-up copies of the specification are filed with the response.
a) The amendments to the specification rectify the deficiencies for the improper use of the term UniProt, Swissprot, nanobodies/nanobody, Sepharose, Tris, Triton, Tween, Alexa, Octet, JetOPTIMUS, GraphPad, c-digit, JETPei, Orbitrap, Nonidet, Dynabead, which is a trade name or a mark used in commerce.
b) The amendments to the specification rectify the deficiencies for failure to recite sequence identifiers for peptide sequences > 4 amino acids in length.
c) The amendments to the specification delete the embedded hyperlink and/or other form of browser-executable code.
d) The amendment to the specification enters the sequence identifiers for the amino acid sequences depicted in the figure.
e) The amendment to the specification corrects the phrases that are overlapping “FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4 (1)” and “FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4”.
Withdrawal of Rejections
Claim Rejections - 35 USC § 112(b)
7. The rejection of Claims 4-8 and 16 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is moot for the canceled claims (Claims 4-6) and withdrawn for the pending claims (7-8). Pending claims 7-8 are amended to depend from claim 1.
Claim Rejections - 35 USC § 112(d)
8. The rejection of Claim 12 under 35 U.S.C. 112 (d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form is moot for the canceled claim.
Claim Rejections - 35 USC § 112(a)
Written Description
9. The rejection of Claims 1-5, 7, 9-16 and 18-19 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 moot for the canceled claims and withdrawn for the pending clams. The amendment of generic claim 1 to incorporate, inter alia, the subject matter of canceled claim 6 obviates the rejection.
Claim Rejections - 35 USC § 103
10. The rejection of Claim(s) 1, 3-5, 12-16 and 18 under 35 U.S.C. 103 as being unpatentable over Rebollo et al (US 20220154153; priority 3/22/2019) is moot for the canceled claims and withdrawn for the pending claims. The amendment of generic claim 1 to incorporate, inter alia, the subject matter of canceled claim 6 obviates the rejection.
Double Patenting
11. The provisional rejection of Claims 1-4, 9-10, 12, 14-16 and 18-19 on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 6-17, 23-26 of copending Application No. 17/802,388 (reference application US 20230220019) is moot for the canceled claims and withdrawn for the pending claims. The amendment of generic claim 1 to incorporate, inter alia, the subject matter of canceled claim 6 obviates the rejection. Note that no terminal disclaimers are of record for the reference application, now US 12565520 B2.
Withdrawn-in-part/ Maintained-in-part
Claim Objections
12. The objection to Claims 1, 3, 6, 9-12 and 16 because of informalities is:
moot for the canceled claims;
withdrawn for the pending claims amended to recite “microtubules a cell” (Claim 1); to replace “in cells” with “in cellulo” (claims 3 and 9-11); to replace “interacting” and “reacting” with “contacting” (claim 16); and to recite “ii) detecting the localization and distribution of the LRRK2 allosteric modulator of i) in said biological sample” (claim 16); and
maintained for
b) Claim 3 because the meaning of in cellulo versus in vitro is not differentiated by the specification. See the specification teaching an in cellulo -based assay comprised in vitro:
[0158] In Cellulo Phospho-Rab Assay
[0159] HEK 293T cells were cultured in DMEM (supplemented with 10% Fetal Bovine Serum, 25 mM L-Glutamine and 0.5% Pen/Strep). For the assay, the cells were seeded onto six-well plates and transfected at a confluency of 50-70% with the individual Nb-GFP expression constructs, SF-tagged LRRK2(G2019S) and FLAG-HA Rab29 using a self-made polyethylenimine (PEI)-based transfection reagent [8]. After 48 hrs cells were lysed in lysis buffer [30 mM Tris-HCL (pH7.4), 150 mM NaCl, 0.5% Nonident-P40, complete protease inhibitor cocktail, phosphatase inhibitor cocktail II & III (all Sigma)]. Lysates were cleared by centrifugation at 10,000×g and adjusted to a protein concentration of 1 μg/μl in 1× Laemmli Buffer. Samples were subsequently subjected to SDS PAGE and Western Blot analysis to determine LRRK2 pS1292 and Rab10 T72 phosphorylation levels, as described below. Total LRRK2 and Rab10 levels were determined as a reference.
d) Claim 16 because the claim is drawn to two separate inventions:
a method of detecting the presence, absence or protein level of a complex comprising anti-LRRK2 ISVD/LRRK2 in any sample; and
detecting the localization and distribution of an anti-LRRK2 ISVD or a labeled anti-LRRK2 ISVD in any biological sample.
The objection is maintained.
New Grounds for Objection
Specification
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - This application fails to comply with the requirements of 37 CFR 1.821 - 1.825. This application contains a “Sequence Listing” as a PDF file (37 CFR 1.821(c)(2)) or as physical sheets of paper (37 CFR 1.821(c)(3)). A copy of the "Sequence Listing" in computer readable form (CRF) has been submitted; however, the content of the CRF does not comply with one or more of the requirements of 37 CFR 1.822 through 1.824, as indicated in the "Error Report" that indicates the "Sequence Listing" could not be accepted. Refer to attachment or document "Computer Readable Form (CRF) for Sequence Listing – Defective" dated 8/5/2026.
Required response – Applicant must provide:
A replacement "Sequence Listing" part of the disclosure, as described above in item 1); together with
An amendment specifically directing its entry into the application in accordance with 37 CFR 1.825(b)(2);
A statement that the "Sequence Listing" includes no new matter as required by 37 CFR 1.825(b)(5); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(b)(4).
If the replacement "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, Applicant must also provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter and
An amendment to the specification to remove the “Sequence Listing previously submitted as a PDF file (37 CFR 1.821(c)(2)) or as physical sheets of paper (37 CFR 1.821(c)(3))
If the replacement "Sequence Listing" part of the disclosure is submitted according to item 1) c) or d) above, Applicant must also provide:
A CRF in accordance with 1.821(e)(1) or 1.821(e)(2) as required by 37 CFR 1.825(b)(6)(ii); and
Statement according to item 2) a) or b) above.
Claim Objections
14. Claims 1-3, 7-11, 13-16, and 18-19 are objected to because of the following informalities:
a) Claims 1-3, 7-11, 13-16, and 18-19 are objected to for reciting “annotated” in Claim 1. Amend claim 1 to replace “annotated” with “numbered” as shown in the specification at
[0037] Amino acid numbering according to Kabat. As an example of different CDR annotations possible for the Nbs disclosed herein, the regions corresponding to alternative CDR annotations (AbM, Chothia, Kabat, IMGT), as compared to the currently used one, are labelled in grey. Llama germline hallmark residues in bold/underlined.
b) Claims 1-3, 7-11, 13-16, and 18-19 are objected to for reciting “microtubules a cell” in Claim 1. This appears to be a typographical error.
Appropriate correction is required.
New Grounds for Rejection
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
15. Claim 16 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 16 for the “wherein” clause is not further limiting by reciting within the same limitation “a biological sample.” The second occurrence of “a biological sample” should recite “said biological sample.”
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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
16. Claims 1-3, 7-11, 13-16, and 18-19 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 claim(s) contains 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.
Claims 1-3, 7-11, 13-16, and 18-19 are drawn to variants for the ISVDs comprising only the CDR1-3 of the sequences for SEQ ID NOs: 1 to 19 that are required to prevent the association of the ISVD variant-bound LRRK2 with microtubules in any cell (Claim 1) and at a KD value for binding the LRRK2 at about 200 nM or lower.
Applicants have not shown themselves to be in possession for the genus of ISVD variants having the structure/function correlation required of the claimed invention.
In addition, and as regards the term “about”, the specification does not provide a definition for the meaning of the term. MPEP (III)(A)
A.“About”
In determining the range encompassed by the term “about,” one must consider the context of the term as it is used in the specification and claims of the application. Ortho-McNeil Pharm., Inc. v. Caraco Pharm. Labs., Ltd., 476 F.3d 1321, 1326, 81 USPQ2d 1427, 1432 (Fed. Cir. 2007). In W.L. Gore & Associates, Inc.v.Garlock, Inc., 721 F.2d 1540, 220 USPQ 303 (Fed. Cir. 1983), the court held that a limitation defining the stretch rate of a plastic as “exceeding about 10% per second” is definite because infringement could clearly be assessed through the use of a stopwatch. However, in another case, the court held that claims reciting “at least about” were invalid for indefiniteness where there was close prior art and there was nothing in the specification, prosecution history, or the prior art to provide any indication as to what range of specific activity is covered by the term “about.” Amgen, Inc. v.Chugai Pharmaceutical Co., 927 F.2d 1200, 18 USPQ2d 1016 (Fed. Cir. 1991).
The POSA cannot reasonably ascertain the full scope of the variant ISVDs that meet the structure/function correlation much less within the meaning of the term “about.” For a specific feature with respect to the KD values. The examiner’s search of the specification for each of the limitations does not identify literal support for these limitations. (MPEP 706.03(m) states in part "New matter includes not only the addition of wholly unsupported subject matter, but may also include adding specific percentages or compounds after a broader original disclosure, or even the omission of a step from a method. See MPEP § 608.04 to § 608.04(c). See In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976) and MPEP § 2163.05 for guidance in determining whether the addition of specific percentages or compounds after a broader original disclosure constitutes new matter.”)
Conclusion
17. No claims are allowed.
18. Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
19. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LYNN A. BRISTOL whose telephone number is (571)272-6883. The examiner can normally be reached Mon-Fri 9 AM-5 PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Wu Julie can be reached at 571-272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/LYNN A BRISTOL/Primary Examiner, Art Unit 1643
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