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.
Claims 1-16, 18-19 and 21-22 are all the claims.
Election/Restrictions
2. Applicant’s election without traverse of Group I in the reply filed on 11/20/2025 is acknowledged.
3. Claims 21-22 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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.
4. Claims 1-16 and 18-19 are the claims under examination.
Priority
5. 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
6. As of 1/4/2026, 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.
7. 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.
Objections
Drawings
8. The drawing sheet for Figure 2A-2C is objected to because the use of the term nanobodies, which is a trade name or a mark used in commerce, has been noted.
The drawing sheet for Figure 15 is objected to because the use of the term Dynabeads, which is a trade name or a mark used in commerce, has been noted.
The 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.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
9. The abstract of the disclosure is objected to because it contains legal phraseology “such as”.
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A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
10. The disclosure is objected to because of the following informalities:
a) The 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, has been noted in this application. The 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.
b) The specification contains peptide sequences > 4 amino acids in length that pursuant to 37 CFR 1.821-1.825 are required to be identified by SEQ ID NO. See “(G4S)x”, “LPETGG”, “GGGYK”.
c) The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. See p. 26. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
d) The legend for Figure 10 fails to include the sequence identifiers for the amino acid sequences depicted in the figure.
e) The specification teaches two phrases that are overlapping “FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4 (1)” and “FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4” yet distinct. The specification does not define or explain a distinction whilst one phrase concludes with “(1).”
Appropriate correction is required.
Claim Objections
11. Claims 1, 3, 6, 9-12 and 16 are objected to because of the following informalities:
a) Claims 1, 3, and 9-12 recite “cells” or “a cell”. Amend the claims to clarify the plurality of the cells in depending from claim 1, and that they are the same cells. Accordingly, amend claims 3 and 9-12 to recite “the cells” to comport with claim 1.
b) Claim 3 is unclear for the phrase “in cells and/or in vitro.” Bioassays taught in the specification comprise cells, in vitro. See [0108]
Such labelled LRRK2 allosteric modulators, such as LRRK2-specific ISVDs or Nanobodies as described herein may for example be used for in vitro, in vivo or in situ assays (including immunoassays known per se such as ELISA, RIA, EIA and other “sandwich assays”, etc.) as well as in vivo imaging purposes, depending on the choice of the specific label.
The POSA cannot reasonably ascertain whether “cells” refers to being, in vivo and/or in vitro.
c) Amend claim 6 to replace “annotated” with “numbered” as regards the numbering system. See
[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.
[0083] It should be noted that—as is well known in the art for VH domains and for VHH domains—the total number of amino acid residues in each of the CDRs may vary and may not correspond to the total number of amino acid residues indicated by the Kabat numbering (that is, one or more positions according to the Kabat numbering may not be occupied in the actual sequence, or the actual sequence may contain more amino acid residues than the number allowed for by the Kabat numbering). This means that, generally, the numbering according to Kabat may or may not correspond to the actual numbering of the amino acid residues in the actual sequence. The total number of amino acid residues in a VH domain and a VHH domain will usually be in the range of from 110 to 120, often between 112 and 115. It should however be noted that smaller and longer sequences may also be suitable for the purposes described herein.
d) Claim 16 is objected to as being drawn to two distinct 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.
e) Amend claim 16 to replace “interacting” and “reacting” with “contacting.”
f) Amend claim 16 to recite “ii) detecting the localization and distribution of the LRRK2 allosteric modulator of i) in said biological sample.”
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
12. Claims 4-8 and 16 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.
a) A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c).
In the present instance, claim 4 recites the broad recitation “an antibody”, and the claim also recites “an antibody mimetic, a single domain antibody, an immunoglobulin single variable domain (ISVD). or an active antibody fragment”, which is the narrower statement of the range/limitation.
In the present instance, claim 4 recites the broad recitation “a chemical compound”, and the claim also recites “a small molecule”, which is the narrower statement of the range/limitation.
The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
d) Claims 5-8 and 16 are indefinite for the phrase “according to the following formula (1): FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4 (1)” in claim 5. The meaning of the term “(1)” within the structure of the formula is unclear and not defined in the specification. See [0197].
Note further, the specification provides another phrase at [0011 and 0058] as “the general structure or sequence of an immunoglobulin variable domain can be indicated as follows: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4.” Clarification is requested.
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.
13. Claim 12 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 12 depends from claim 1 and recites “wherein the allosteric modulator prevents LRRK2 association to microtubules in a cell.”
Claim 1 recites “wherein the allosteric modulator, when bound to LRRK2, prevents the association of the bound LRRK2 with microtubules in cells.”
Claim 12 is not further narrowing from claim 1.
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
14. Claims 1-5, 7, 9-16 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.
A) Claims 1-4, 9-13, and 18-19 are drawn to incalculable of known-and-yet-to-be-discovered allosteric modulators that specifically bind human LRRK2 that upon binding prevent the association of the binding complex with microtubules in any cell.
The structure function/correlation that is required of the genus of LRRK2 allosteric modulators for the instant claims, and absent a concise definition of the structure(s) in claim 1, are the following: prevents the association of the bound LRRK2 with microtubules in cells (claim 1); the KD value of the allosteric modulator for binding LRRK2 is in the range of about 200 nM or lower (claim 2); affects LRRK2 kinase activity in cells and/or in vitro (claim 3); inhibits LRRK2 kinase activity in cells (claim 9); inhibits LRRK2 substrate phosphorylation in cells (claim 10); increases LRRK2 kinase activity in cells (claim 11); and prevents LRRK2 association to microtubules in a cell (claim 12).
MPEP 2163(I)(A) stating in part:
An 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 example, the amino acid sequence of a protein along with knowledge of the genetic code might put an inventor in possession of the genus of nucleic acids capable of encoding the protein, but the same information would not place the inventor in possession of the naturally-occurring DNA or mRNA encoding the protein. See In re Bell, 991 F.2d 781, 26 USPQ2d 1529 (Fed. Cir. 1993); In re Deuel, 51 F.3d 1552, 34 USPQ2d 1210 (Fed. Cir. 1995) (holding that a process could not render the product of that process obvious under 35 U.S.C. 103). (For guidance on subject matter eligibility of claims to naturally-occurring compositions, see MPEP § 2106.) The Federal Circuit has pointed out that, under United States law, a description that merely renders a claimed invention obvious may not sufficiently describe the invention for the purposes of the written description requirement of 35 U.S.C. 112. See Eli Lilly, 119 F.3d at 1567, 43 USPQ2d at 1405; compare Fonar Corp. v. Gen. Elec. Co., 107 F.3d 1543, 1549, 41 USPQ2d 1801, 1805 (Fed. Cir. 1997) (“As a general rule, where software constitutes part of a best mode of carrying out an invention, description of such a best mode is satisfied by a disclosure of the functions of the software. This is because, normally, writing code for such software is within the skill of the art, not requiring undue experimentation, once its functions have been disclosed.... Thus, flow charts or source code listings are not a requirement for adequately disclosing the functions of software.”).
Applicants have failed to show the existence of LRRK2-specific allosteric modulators, that meet the claimed functional properties required of the claims. A skilled artisan cannot, as one can do with a fully described genus, visualize or recognize the identity of the members of the genus that exhibit the functional properties. The Court has held that the disclosure of screening assays and general classes of compounds was not adequate to describe compounds having the desired activity: without disclosure of which peptides, polynucleotides, or small organic molecules have the desired characteristic, the claims failed to meet the description requirement of § 112. See University of Rochester v. G.D. Searle & Co., lnc., 69 USPQ2d 1886,1895 (Fed. Cir. 2004).
Here is the case, where the application as whole is not designed to guide the POSA in the generation/making and use of just any allosteric modulators that specifically bind human LRRK2 while leaving LRRK2 subcellular localization unaffected. Here is the case, where the abstract defines protein agents for allosteric modulation of LRRK2 kinase activity comprising immunoglobulin single variable domains (ISVDs) binding to human LRRK2 with nanomolar affinity. Here is the case, that the specification provides the specific characterization of 19 anti-LRRK2 ISVDs (Tables 3 and 4; nanobodies (Nbs)) for their effects on the LRRK2 protein activity, in vitro (Examples 5-11).
B) Claims 1, 5, 7 and 16 are drawn to the allosteric modulator comprising an immunoglobulin single variable domain (ISVD), comprising 4 framework regions (FR) and 3 complementarity-determining regions (CDR) according to the following formula (1): FR1- CDR1-FR2-CDR2-FR3-CDR3-FR4 (1) (claim 5); the combination of CDR 1, 2 and 3 sets (claim 7); and an in vitro method of detection for hLRRK2 in a sample (claim 16).
Because applicant seeks patent protection for all such anti-LRRK2 ISVDs, the genus must be adequately described. A description adequate to satisfy 35 U.S.C. § 112(a) must clearly allow persons of ordinary skill in the art to recognize that the inventor invented what is claimed (Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en banc) (citation omitted, alteration in original). The purpose of the written description requirement is to “ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent’s specification” (In re Katz Interactive Call Processing Patent Litig. 639 F.3d 1303, 1319 (Fed. Cir 2011).
State of the Relevant Art
AS regards claims 5, 7 and 16, it was well-established in the art that the formation of an intact antigen-binding surface on an antibody required the association of the complete heavy and light chain variable regions, 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 (Almagro & Franssen, Frontiers in Bioscience, 13:1619-33 (2008) (PTO-892) (see Section 3 “Antibody Structure and the Antigen Binding Site” and Figure 1). While this overall architecture is shared among antibodies from a wide variety of sources (human, rat, mouse, rabbit), the structure each antibody uses to bind its particular epitope on an antigen is structurally distinct and is formed by a recombination event that results in high variability at the amino acid sequence level, even when the same antigen is bound (Edwards et al., J Mol Biol 334:103-118 (2003) (PTO-892); see also Marchalonis et al., Dev & Comp Immunol. 30:223-247 (2006) (PTO-892), summarized in Abstract and Conclusion.
Methods of preparing antibodies from a variety of species to a protein or peptide of interest were well-established in the art at the time the invention was made. But application of those methods to any given antibody was still a matter of trial-and-error testing, and the skilled person could not automatically predict which residues in the CDRs would be tolerant of mutations, or which amino acid substitutions would maintain antigen binding. Overall, at the time the invention was made, the level of skill for preparing antibodies and then selecting those antibodies with desired functional properties was high. For example, it is generally the case that absent the fundamental structure provided for by all six CDRs of a parental antibody in the context of appropriate VH and VL framework sequences, a person of ordinary skill cannot visualize or otherwise predict, what an antibody with a particular set of functional properties would look like structurally.
Moreover, persons of ordinary skill in the art have long since acknowledged that even minor changes in the amino acid sequences of the VH and VL, particularly in the CDRs, may dramatically affect antigen-binding function. Lippow, for example, teaches that a single point mutation in the CDR of a parent antibody led to as much as an eightfold improvement in binding affinity in the resulting mutant (p. 1172, left col., lines 7-8 from end of first full paragraph and Table 1a) (Lippow et al., “Computational design of antibody-affinity improvement beyond in vivo maturation,” Nature Biotechnology, 25(10):1171-1176 (2007) (PTO-892).
Sulea teaches that individual point mutations gave an improvement of one order of magnitude in binding affinity, which in turn, generated a 6-fold enhancement of efficacy at the cellular level (Abstract) (Sulea et al., “Application of Assisted Design of Antibody and Protein Therapeutics (ADAPT) improves efficacy of a Clostridium difficile toxin A single-domain antibody," Scientific Reports, 8(260):1-11 (2018) (PTO-892). Hasegawa et al. reports that a single amino acid substitution in the variable region was sufficient to alter the efficiency of biosynthesis and the variant antibody acquired stronger binding affinity to its antigen than the parent (Hasegawa et al., “Single amino acid substitution in LC-CDR1 induces Russell body phenotype that attenuates cellular protein synthesis through elF2a phosphorylation and thereby downregulates IgG secretion despite operational secretory pathway traffic,” MABS, VOL. 9, NO. 5, pp. 854-873 (2017) (PTO-892)). Altshuler teaches that generally, “CDR mutations should not involve residues that can play structural functions (form parts of the domain ‘internal core’, internal salt bridges, hydrogen bonds, etc.).” “Usually these are conservative residues, and any substitution of these residues causes decrease[s] in affinity” (Altshuler et al., “Generation of Recombinant Antibodies and Means for Increasing Their Affinity,” Biochemistry (Moscow), 75(13):1584-1605 (2010) at p. 1600, col. 1, para. 2, lines 1-5 (PTO-892). Accordingly, a person of ordinary skill in the art would have recognized that it was highly unpredictable that any of the CDRs or FRs could be modified to create an unlimited change in amino acids for both the CDRs and FRs of the claimed antibodies, without increasing, eliminating, or in some way altering antigen binding.
Summary of species disclosed in the specification
Applicant’s specification fully discloses 19 ISVDs: the VH/VL CDRs from the anti-LRRK2 VHH antibodies of SEQ ID NOS 1-19 are supported in Table 4:
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Are the disclosed species representative of the claimed genus?
It is asserted that the disclosed species are not representative of the claimed genus of ISVDs. The genus of all possible anti-LRRK2 antibodies much less ISVDs encompassed by the claimed CDR variation (see especially claim 7) would be structurally distinct but unpredictable whether the structure/function correlation was met for binding to hlRRK2. The specification does not identify which CDRs, which combination of the CDRs, or which subset of residues in the combination of CDRs is essential for the recited function of binding hLRRK2. Neither the specification nor the prior art provides guidance as to what structural changes can be made to the parent sequences and still predictably arrive at an ISVD that binds hLRRK2. The disclosed species therefore do not represent the claimed genus.
Has Applicant provided a common structure sufficient to visualize the genus?
Antibodies much less ISVDs are not understood well enough to allow researchers to predict with certainty what modifications can be made to a primary antibody sequence such that binding is maintained. “[T]he major test of understanding is whether the changes associated with antibody maturation can be predicted with any reasonable accuracy, and whether there is sufficient information for developing therapeutic antibodies,” Vajda et al., “Progress toward improved understanding of antibody maturation,” Current Opinion in Structural Biology, 67 pp. 226-231 (2021 (PTO 892)) at p. 226, col. 2, lines 20-24.
As recently as 2020, researchers were still speculating as to how to reliably identify further putative binders from antibody sequence data, see, e.g., Marks et al., “How repertoire data are changing antibody science,” J. Biol. Chem. 295(29) 9823-9837 (2020 (PTO 892)), acknowledging that “there is a vast amount of the antibody sequence space that remains unknown,” p. 9831, col. 2, para. 2.
Even though the protein sequence of hLRRK2 was known in the art, this would not have translated into knowledge of the genus of antibodies much less ISVDs that could possibly engage it. Computational and machine learning approaches for sequence-based prediction of paratope-epitope interactions are accumulating, but “it remains unclear whether antibody-antigen binding is predictable” (Akbar et al., Cell Reports 34, 108856, Mar. 16, 2021 at p. 2, col. 2, para. 2 (PTO 892)). The current state of the art continues to work toward finding an effective and efficient prediction tool for reliably assigning antibody structure based on known target epitopes. See e.g., Lo et al., “Conformational epitope matching and prediction based on protein surface spiral features,” BMC Genomics volume 22, Article number: 116 (2021 (PTO 892)) (disclosing new algorithms that calculate physicochemical properties, such as polarity, charge or the secondary structure of residues within the targeted protein sequences, and then applying quantitative matrix analyses or machine-learning algorithms to predict linear and conformational epitopes).
C) Claims 14-15 are drawn to nucleic acid molecules and vectors encoding the LRRK2 allosteric modulator. Notably, the implication of encoding the modulators is that they are amino acid-based yet without structure that corresponds to the required function of at least claim 1. See the rejections set forth under section A) hereinabove as they apply to the analysis of claims 14-15.
It is asserted that neither the specification nor the state of art at the time of filing disclosed structural features common to the members of the genus of allosteric modulators that specifically bind hLRRK2 and prevent the association of the modulator/hLRRK2 complex with cellular microtubules for reliably assigning different structures, which supports the premise that the inventors DID NOT possess the full scope of the claimed invention at the time of filing.
Claim Rejections - 35 USC § 103
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 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.
15. Claim(s) 1, 3-5, 12-16 and 18 is/are rejected under 35 U.S.C. 103 as being unpatentable over Rebollo et al (US 20220154153; priority 3/22/2019).
The claim interpretation is discussed at length and in depth as herein above and throughout the Office Action.
Claims 1, 3-5, 12-16 and 18 are prima facie obvious over Rebollo.
Rebollo teaches new inhibitors of LRRK2/ serine/threonine protein phosphatase 1 (PP1) interactions where as evidenced by Liao, PPI activity is associated with microtubules (MT).
Robello teaches peptides identified on LRRK2 that is involved in the interaction with PP1, wherein the peptides are from residues 1701-1718 of LRRK2 (paragraph 0066). As evidenced by the instant specification, residues 1701-1718 is in the COR-B domain, which is involved in binding to microtubules (figure 1; page 27).
Robello teaches a specific family of peptides that, by inhibiting PP1-LRRK2 interaction provides valuable candidates in treating neurological disorders [0006]; and that “experimental data show that, in vitro, peptides of the invention are able to compete with LRRK2/PP1 interaction, and, in cellulo, are internalized within cells thereby exhibiting biological effects as, for example in neuronal cells, an improvement in neurite outgrowth” [0007]. Accordingly, where the inhibitors compete with the LRRK2/ PP1 interaction, the LRRK2 is not bound to microtubules. See instant claims 1, 3-4 (peptides) and 12.
Robello teaches antibody inhibitors at [0096] In another embodiment, a composition of the invention comprises at least one agent inhibitor of LRRK2/PP1 interaction selected from an aptamer or an antibody as described above. See instant claim 4 (antibody).
Robello teaches single domain antibody inhibitors at [0069] single domain antibodies (DABs). See instant claim 5.
Regarding claims 4 and 5, Robello also teaches antibodies that binds to the peptides (paragraph 0069), thus Robello teaches antibodies that binds to LRRK2 in the COR-B domain. Regarding claim 13, Robello teaches multivalent antibody constructs at [0074].
Robello teaches multivalent antibody constructs at [0074]. See instant claim 13.
Robello teaches nucleic acids and vectors at [0018] In another particular aspect, the invention relates to a nucleic acid molecule encoding for the peptide of the invention and in furthers aspects, to a vector which comprises said nucleic acid molecule or a host cell transformed with said nucleic acid or vector. See instant claims 14-15.
Robello teaches detection of LRRK2 protein in a sample at [0026] FIG. 3: Internalization of FITC labelled peptides of the invention in primary cells. A. in Peripheral Blood Mononuclear Cells (PBMC) of healthy human. B. in PBMC of chronic lymphocytic leukemia (CLL). FACS analysis: No FITC containing cells is detected in control samples (“control”: control cells, not incubated with any peptide), whereas a majority of FITC labelled cells is detected for cell samples incubated with either of FITC labelled peptide 13 or 14. See instant claim 16.
Robello teaches pharmaceutical compositions at [0099] A composition according to the invention typically comprises one or several pharmaceutically acceptable carriers or excipients. Also, for use in the present invention, compounds of the invention are usually mixed with pharmaceutically acceptable excipients or carriers. In this regard, in a particular embodiment a composition according to the invention is a pharmaceutical composition comprising said peptide and/or agent inhibitor of LRRK2/PP1 interaction as exposed above. See instant claim 18.
It would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention that the LRRK2 peptides of Robello would inhibit the binding of LRRK2 to microtubules, because the LRRK2 peptides are located in the COR-B domain, and as evidenced by the instant specification the COR-B domain of LRRK2 interacts with microtubules.
Further, it would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention that the antibody that binds to residues 1701-1718 of LRRK2 will cause an allosteric change on LRRK2 and inhibit binding to microtubules, because as evidenced by the instant specification 1701-1718 of LRRK2 is part of the COR-B domain that is important for binding to microtubules.
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.
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16. Claims 1-4, 9-10, 12, 14-16 and 18-19 are provisionally rejected 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). The ref application is not afforded safe harbor under 35 USC 121 because it shares no continuity nor a restriction/ speciation with the claims of the instant application.
Ref generic claim 1 is drawn to a synthetic peptide for the inhibition or modulation of the activity of LRRK2.
1. (Original) A synthetic polypeptide comprising an amino acid sequence having an α- helical shape that mimics the Ras of complex proteins (ROC) domain of leucine-rich repeat kinase 2 (LRRK2), wherein the polypeptide comprises at least one pair of non-natural amino acids inserted into the amino acid sequence that are cross-linked to stabilize the a-helical shape.
MPEP 804 (II)(B)(1) stating in part:
The specification can be used as a dictionary to learn the meaning of a term in the claim. Toro Co. v. White Consol. Indus., Inc., 199 F.3d 1295, 1299, 53 USPQ2d 1065, 1067 (Fed. Cir. 1999) (“[W]ords in patent claims are given their ordinary meaning in the usage of the field of the invention, unless the text of the patent makes clear that a word was used with a special meaning.”); Renishaw PLC v. Marposs Societa' per Azioni, 158 F.3d 1243, 1250, 48 USPQ2d 1117, 1122 (Fed. Cir. 1998) (“Where there are several common meanings for a claim term, the patent disclosure serves to point away from the improper meanings and toward the proper meanings.”). “The Patent and Trademark Office (‘PTO’) determines the scope of the claims in patent applications not solely on the basis of the claim language, but upon giving claims their broadest reasonable construction ‘in light of the specification as it would be interpreted by one of ordinary skill in the art.’ ” Phillips v. AWH Corp., 415 F.3d 1303, 1316, 75 USPQ2d 1321, 1329 (Fed. Cir. 2005) (en banc) (quoting In re Am. Acad. of Sci. Tech. Ctr., 367 F.3d 1359, 1364, 70 USPQ2d 1827, 1830 (Fed. Cir. 2004); see also MPEP § 2111.01.
To avoid improperly treating what is disclosed in a reference patent or copending application as if it were prior art in the context of a nonstatutory double patenting analysis, the examiner must first properly construe the scope of the reference claims. The portion of the specification of the reference that describes subject matter that falls within the scope of a reference claim may be relied upon to properly construe the scope of that claim. In particular, when ascertaining the scope of the reference’s claim(s) to a compound, the examiner should consider the reference’s specification, including all of the compound’s uses that are disclosed. See Sun Pharm. Indus., 611 F.3d at 1386-88, 95 USPQ2d at 1801-02.
Whilst the reference LRRK2 peptide modulators (dimerization disruptor peptides [0145]) are used in methods of treatment, the activit(ies) of the peptides while not recited in the claims are otherwise inherent.
The ref specification teaches:
[0008] The differentiating potential in therapeutic approaches of the LRRK2 allosteric modulators of the present disclosure is therefore expected to emerge from its more precise and/or highly specific effect on LRRK2 activity without further disturbing vesicular membrane transport or other downstream effects caused by relocalized LRRK2 bound to microtubules. See instant claims 1, 3-4 and 12.
[0014] FIGS. 2A-2C show LCIP1 and LRIP4 bind LRRK2 in vitro and downregulate LRRK2 dimerization. In FIG. 2A, that fluorescence polarization assays indicated that while LRIP4 bound its RocCOR target with a K.sub.D of approximately 50 nM, LCIP1 bound its CORB target with considerably less affinity with a K.sub.D of 1 μM. See instant claim 2.
[0132] Thus, preliminary data from these experiments demonstrate that the stapled peptide tested is cell permeable, nearly completely blocks LRRK2 dimerization and downregulates LRRK2 kinase activity. See instant claim 9.
[0016] FIGS. 4A-4E show that LCIP1 and LRIP4 inhibit LRRK2 autophosphorylation and Rab10 phosphorylation. LRIP4 demonstrated inhibition of Rab10 phosphorylation. See instant claim 10.
[0052] Peptides and peptidomimetics can be prepared by any method, such as by synthesizing the peptide or peptidomimetic, or by expressing a nucleic acid encoding an appropriate amino acid sequence in a cell and harvesting the peptide from the cell. Of course, a combination of such methods also can be used. See instant claim 14.
[0054] Alternatively, the peptide may be synthesized using recombinant techniques. In this case, a nucleic acid encoding the peptide is cloned into an expression vector under the control of expression control sequences (e.g., a promoter, a terminator and/or an enhancer) allowing its expression. The expression vector is then transfected into a host cell (e.g., a human, CHO, mouse, monkey, fungal or bacterial host cell), and the transfected host cell is cultivated under conditions suitable for the expression of the peptide. Standard recombinant DNA and molecular cloning techniques are described, for example, in: Sambrook and Maniatis, Molecular Cloning: A Laboratory Manual, Second Edition, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1989); Silhavy et al., Experiments with Gene Fusions, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1984); and Ausubel et al., Current Protocols in Molecular Biology, published by Greene Publishing Assoc. and Wiley-Interscience (1987). See instant claims 14-15.
[0014] FIGS. 2A-2C show LCIP1 and LRIP4 bind LRRK2 in vitro and downregulate LRRK2 dimerization. In FIG. 2A, that fluorescence polarization assays indicated that while LRIP4 bound its RocCOR target with a K.sub.D of approximately 50 nM, LCIP1 bound its CORB target with considerably less affinity with a K.sub.D of 1 μM. Both scrambled peptide controls exhibited no binding. Each data point is representative of n=3. In FIG. 2B, shows that lysates derived from HEK293 cells overexpressing GFP-tagged LRRK2 were treated with 10 μM biotin-labeled peptides (LCIP1 and LRIP4) and pulldowns were performed using avidin-coated resin. LRRK2 was detected via immunoblotting, demonstrating that both peptides bound LRRK2. Blot is representative of n=3. In FIG. 2C, HEK293 cells were transiently transfected with Strep-tagged LRRK2 and GFP or GFP-tagged LRRK2. Whereas Strep-LRRK2 did not bind non-specifically to GFP, it was pulled down with GFP-LRRK2. Incubation with inhibitory peptides LRIP4 and LCIP1 resulted in reduced dimerization. GFP alone is indicated in the bottom panel. Blot is representative of n=3. See instant claim 16.
[0055] The method of producing the peptide may optionally comprise the steps of purifying said peptide, chemically modifying said peptide, and/or formulating said peptide into a pharmaceutical composition. See instant claim 18.
[0178] To test whether impaired LRRK2 dimerization may result in attenuation of S1292 autophosphorylation, HEK293 cells were transfected with GFP-tagged LRRK2. Twenty-four hours post transfection, cells were treated with 10 μM of either LRIP4 or LCIP1 for a 12-hour window. Immunoblotting analysis of pS1292-LRRK2 revealed that both peptides caused a significant reduction of autophosphorylation by 5 0-7 0% as compared to the DMSO control, although neither was as effective as the ATP-competitive inhibitor MLi-2 (FIGS. 4A and 4B). See instant claim 19.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
17. No claims are allowed.
18. 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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LYNN ANNE BRISTOL
Primary Examiner
Art Unit 1643
/LYNN A BRISTOL/Primary Examiner, Art Unit 1643